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\begin{document}

\title{The Role of TFIIH Complex in Nucleotide Excision Repair}



\author[1]{Allyson Hoag}%
\author[1]{Mingrui Duan}%
\author[1]{Peng Mao}%
\affil[1]{University of New Mexico}%


\vspace{-1em}



  
  \date{May 19, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
DNA damage occurs throughout life from a variety of sources, and it is
imperative to repair damage in a timely manner to maintain genome
stability. Thus, DNA repair mechanisms are a fundamental part of life.
Nucleotide Excision Repair (NER) plays an important role in the removal
of bulky DNA adducts, such as cyclobutane pyrimidine dimers (CPDs) from
ultraviolet (UV) light or DNA crosslinking damage from platinum-based
chemotherapeutics, such as cisplatin. A main component for the NER
pathway is transcription factor IIH (TFIIH), a multifunctional,
10-subunit protein complex with crucial roles in both transcription and
NER. In transcription, TFIIH is a component of the pre-initiation
complex (PIC) and is important for promoter opening and the
phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH
is important for DNA unwinding, recruitment of downstream repair
factors, and verification of the bulky lesion. Several different disease
states can arise from mutations within subunits of the TFIIH complex.
Most strikingly are Xeroderma Pigmentosum (XP), XP combined with
Cockayne Syndrome (CS), and Trichothiodystrophy (TTD). Here, we
summarize the recruitment and functions of TFIIH in the two NER
subpathways, global genomic (GG-NER) and transcription-coupled NER
(TC-NER). We will also discuss how TFIIH's roles in the two subpathways
lead to different genetic disorders.%
\end{abstract}%



\sloppy


\textbf{The Role of TFIIH Complex in Nucleotide Excision Repair}

Allyson Hoag, Mingrui Duan, Peng Mao*

Department of Internal Medicine, University of New Mexico Comprehensive
Cancer Center University of New Mexico, Albuquerque, NM 87131, USA

*Corresponding author: Peng Mao (PMao@salud.unm.edu)

\textbf{Key words:} DNA damage, genome stability, transcription factor
IIH, GG-NER, TC-NER

\textbf{Abstract}

DNA damage occurs throughout life from a variety of sources, and it is
imperative to repair damage in a timely manner to maintain genome
stability. Thus, DNA repair mechanisms are a fundamental part of life.
Nucleotide Excision Repair (NER) plays an important role in the removal
of bulky DNA adducts, such as cyclobutane pyrimidine dimers (CPDs) from
ultraviolet (UV) light or DNA crosslinking damage from platinum-based
chemotherapeutics, such as cisplatin. A main component for the NER
pathway is transcription factor IIH (TFIIH), a multifunctional,
10-subunit protein complex with crucial roles in both transcription and
NER. In transcription, TFIIH is a component of the pre-initiation
complex (PIC) and is important for promoter opening and the
phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH
is important for DNA unwinding, recruitment of downstream repair
factors, and verification of the bulky lesion. Several different disease
states can arise from mutations within subunits of the TFIIH complex.
Most strikingly are Xeroderma Pigmentosum (XP), XP combined with
Cockayne Syndrome (CS), and Trichothiodystrophy (TTD). Here, we
summarize the recruitment and functions of TFIIH in the two NER
subpathways, global genomic (GG-NER) and transcription-coupled NER
(TC-NER). We will also discuss how TFIIH's roles in the two subpathways
lead to different genetic disorders.

\textbf{1. Introduction}

DNA damage occurs frequently throughout all aspects of life from a
variety of sources. Exogenous DNA damaging sources include physical or
chemical agents, such as ionizing radiation, UV light, environmental
mutagens, or chemotherapeutic treatments. These exogenous agents induce
DNA strand breaks, helix-distorting photolesions, and intra- or
inter-strand crosslinks (Chatterjee \& Walker, 2017). There are also
many damaging agents residing in cells. The most common one is reactive
oxygen species (ROS), which is generated during cell metabolism and can
induce high amount of oxidative damage in DNA (Cooke et al., 2003).
Additionally, cytosine deamination (loss of an amino group),
depurination (loss of a base), and nucleotide misincorporation during
replication or recombination also occur at high frequency to form
endogenous DNA damage (Ciccia \& Elledge, 2010). These lesions may cause
a variety of structural alterations within the DNA, thereby representing
a major threat to the integrity of the genome.

DNA damage can trigger a wide range of cellular responses, including
gene transcription, checkpoint activation, DNA repair, and others
(Giglia-Mari et al., 2011; J. Y. Wang, 1998). Among these responses, DNA
repair plays particularly important roles in maintaining genome
stability (Sancar et al., 2004). This is because many types of DNA
lesions are genotoxic by blocking DNA replication or gene transcription.
Failure to repair them may lead to apoptosis (J. Y. J. Wang, 2001).
Alternatively, if the cell does not die, the unrepaired damage can lead
to mutations, which can cause several disease states, such as cancer or
neurodegeneration (Chatterjee \& Walker, 2017; Cooke et al., 2003;
Giglia-Mari et al., 2011; Martin, 2008; Sancar et al., 2004).

Corresponding to the different types of DNA damage, cells are equipped
with different repair pathways and are able to utilize the right repair
mechanism for damage removal. There are several DNA repair pathways
currently identified in the cell, including direct damage reversal,
mismatch repair (MMR), base excision repair (BER), nucleotide excision
repair (NER), single strand break repair (SSBR), and double strand break
repair (DSBR) (Chatterjee \& Walker, 2017; Martin, 2008). Direct damage
reversal is exactly what the name implies: a direct reversal of the
damage. Direct reversal repair enzymes include UV photolyase that
repairs UV damage,
O\textsuperscript{6}-methylguanine-DNA-methyltransferase (MGMT) that
repairs O\textsuperscript{6}-alkylated bases, and the AlkB family that
reverses N-alkylated base adducts (Yi \& He, 2013). Direct reversal is
highly specific for the damage type and only requires a single protein
to conduct repair. MMR corrects mismatches between base pairs (i.e.,
non-A:T or G:C pairing) and insertions or deletions accumulated during
replication and recombination. MMR has four major steps: mismatch
recognition by MutS, recruitment of downstream MMR factors such as MutL,
excision of DNA mismatch, and synthesis at the site using the remaining
strand as a template (G.-M. Li, 2008). BER repairs small base damage in
the nucleus and the mitochondria, such as oxidation, deamination, abasic
sites, and alkylation lesions that do not cause distortions to the DNA
helix. Within BER there are short-patch and long-patch pathways,
requiring only a few key enzymes to carry out base excision, DNA
backbone incision, end processing, repair synthesis, and ligation
(Krokan \& Bj\selectlanguage{ngerman}ørås, 2013). SSBR and DSBR are responsible for the repair
of single-stranded and double-stranded breaks, respectively. In SSBR,
breaks are recognized by the Poly (ADP-ribose) polymerase 1 (PARP1)
protein and repair is conducted similar to the BER pathway (Ray
Chaudhuri \& Nussenzweig, 2017). DSBR has two major pathways to resolve
double strand breaks, non-homologous end joining (NHEJ) and homologous
recombination (HR) (Lieber, 2010; Scully et al., 2019).

NER is a versatile repair mechanism that removes a wide range of DNA
adducts and plays a critical role for maintaining genome stability
(Marteijn et al., 2014). Somewhat similar to BER, NER also conducts the
`cut-and-patch' type repair process; however, NER mainly removes
helix-distorting lesions from the genome, such as UV photoproducts --
cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs)
formed by UV light, DNA adducts induced by benzopyrene in cigarettes,
and crosslinks formed by cancer chemotherapeutics, such as cisplatin
(Marteijn et al., 2014). These adducts can present different chemical
modifications within the DNA; however, they are all bulky and helical
distorting and can impede the progression of replication and
transcription. As detailed below, NER performs `dual incision' on both
5' and 3' sides of the damage to remove approximately 25-30 bases (Huang
et al., 1992). The resulting gap on the damaged strand is subsequently
filled by DNA polymerase and ligase (Marteijn et al., 2014; Prakash \&
Prakash, 2000; Schärer, 2013; Spivak, 2015).

Transcription factor IIH (TFIIH) is an essential protein complex for
both transcription initiation and NER (Compe \& Egly, 2012). In DNA
repair, TFIIH mainly functions as a DNA helicase to unwind the two
strands and promote assembly of the NER pre-incision complex.
Additionally, TFIIH also plays a role in damage verification before the
step of strand incision (Mu et al., 2018; Zurita \& Cruz-Becerra, 2016).
Here, we will discuss functions of TFIIH in NER and human genetic
disorders associated with TFIIH deficiency.

\textbf{2. Mechanisms of TFIIH in Regulating NER}

\emph{2.1. The two subpathways in NER}

NER has two subpathways -- global genome (GG-NER) and transcription
coupled NER (TC-NER) (Schärer, 2013; Spivak, 2015). GG-NER utilizes
surveillance proteins such as XPC and UV-DDB to recognize DNA damage.
Therefore, it repairs damage across the whole genome, including
transcribed and untranscribed regions (Kusakabe et al., 2019). In
contrast, TC-NER is specific for repair on the transcribed strand of
active genes, when elongating RNA Pol II is stalled by the damage. While
TC-NER only repairs a small fraction of the human genome, it is more
efficient than GG-NER and can rapidly respond to Pol II stalling for
repair (Duan et al., 2021; Fousteri \& Mullenders, 2008). There are four
main steps in NER: damage recognition, DNA unwinding, dual incision, and
repair synthesis. Although there is a key difference in the damage
recognition step between the two subpathways, the damage recognition is
followed by the recruitment of TFIIH in both of them, and the steps
after TFIIH are believed to be the same as well (Okuda et al., 2017;
Tsutakawa et al., 2020). As GG- and TC-NER are initiated by XPC/UV-DDB
and RNA Pol II, respectively, the mechanism for TFIIH recruitment in the
two subpathways is found to be significantly different (see below for
more details).

Once TFIIH is recruited, it functions as a DNA helicase to promote
pre-incision complex formation together with other NER factors, such as
XPA and RPA (Coin et al., 2008; Kuper et al., 2014; Topolska-Wo\selectlanguage{polish}ś \selectlanguage{english}et al.,
2020). After the DNA strands have been unwound, TFIIH retains the open
DNA conformation (Kokic et al., 2019). ERCC1-XPF and XPG, two repair
endonucleases, nick the damaged strand on the 5' and 3' side,
respectively. XPF and XPG cut the DNA strand asymmetrically relative to
the lesion. ERCC1-XPF cleaves DNA 20 nt \selectlanguage{ngerman}± 5 nt upstream of the damage
site, whereas XPG cleaves DNA 6 nt ± 3 nt downstream of the lesion (Hu
et al., 2015), evicting an oligonucleotide of \textasciitilde{}30nt
containing the damage. A recent study shows that the Rad5-related DNA
translocase HLTF facilitates release of the incised DNA fragment (van
Toorn et al., 2022). Once the damage has been excised, DNA polymerase
can synthesize new nucleotides, followed by ligation into the DNA
strand. This restores the nucleotide sequence for transcription and
replication, and the factors then disassociate from the strand (Schärer,
2013).

As NER plays a critical role in the repair of a variety of DNA damage,
genetic defects and mutations that occur in TFIIH and other NER proteins
are associated with a variety of human disorders (Coin et al., 1998;
Lehmann, 2001). These will be discussed more in detail later in this
paper.

\emph{2.2. Introduction of TFIIH}

TFIIH is a multifunctional 10-subunit protein complex integral to both
NER and transcription. The TFIIH complex includes a 7-subunit core,
which consists of XPB, XPD, p52, p8, p62, p34, and p44, and a
three-subunit cyclin activated kinase (CAK) module, which consists of
CDK7, cyclin H, and MAT1 (Tsutakawa et al., 2020) (\textbf{Figure 1} ).
During transcription, TFIIH is part of the preinitiation complex (PIC)
and functions for promoter opening and RNA Pol II phosphorylation. The
XPB subunit in TFIIH, an ATP-dependent DNA translocase, is particularly
important for opening promoter DNA (Dienemann et al., 2019; Fishburn et
al., 2015). The CAK kinase module in TFIIH phosphorylates Ser5 in RNA
Pol II C-terminal domain to stimulate promoter escape of Pol II from the
initiator element (Helenius et al., 2011; Wong et al., 2014).

However, when damage is recognized by NER surveillance proteins, UV-DDB
and XPC, or the stalling of RNA Pol II, TFIIH is reallocated to damage
for the NER pathway and there will be a decrease in TFIIH
transcriptional activity until the damage is repaired (Coin et al.,
2008). Different from its role in transcription, TFIIH mainly performs
the helicase function to keep open the DNA bubble, and facilitate
recruitment of downstream repair proteins. The helicase function is
solely dependent on the 7-subunit core complex, but does not require the
CAK kinase module. Interestingly, it has been shown that CAK needs to be
displaced from TFIIH by XPA, and the displacement activates the repair
function of TFIIH (Coin et al., 2008). CAK has been shown to negatively
regulate the helicase activity of XPD and also phosphorylate one or more
TFIIH and NER components (Araújo et al., 2000). Therefore, dissociation
of the CAK complex from the TFIIH core can stimulate the helicase and
ATPase activities of other subunits, allowing for the DNA strand to be
opened and enlarged around the site of damage (Winkler et al., 2001). On
the other hand, the p44 subunit interacts with XPD and can enhance XPD's
ATPase activity \emph{in vitro} (Dubaele et al., 2003).

\emph{2.3. TFIIH Recruitment and functions in GG-NER}

GG-NER is responsible for the repair of bulky adducts across the genome,
and is particularly important for the suppression of mutations and
potential carcinogenesis associated with UV lesions and other bulky
adducts. In GG-NER, damage such as a CPD lesion is first recognized by
the UV-DDB protein and then transferred to XPC, through UV-DDB-mediated
XPC polyubiquitylation (Sugasawa et al., 2005). XPC forms a heterodimer
with RAD23 and binds to thermodynamically destabilized DNA (Min \&
Pavletich, 2007), instead of a specific type of lesion. This low lesion
specificity allows GG-NER to repair a broad range of lesions, such as UV
photolesions, cisplatin-induced intrastrand crosslinks, benzopyrene
adducts, and other helix-distorting lesions. However, the low
specificity may enable XPC to bind to other types of damage not commonly
repaired by NER, including DNA mismatch bubbles (Chen et al., 2015; Y.
S. Krasikova et al., 2013). Thus, the importance of TFIIH's damage
verification function is inexplicably tied to the role of XPC to avoid
incisions at sites without bulky adducts.

TFIIH is directly recruited by XPC in GG-NER. Biochemical data indicates
that the p62 and XPB subunits of TFIIH physically interact with XPC
(Uchida et al., 2002; Yokoi et al., 2000). This finding is further
supported by the structural data for the yeast XPC-TFIIH-DNA complex,
which shows that the N-terminus of XPC contacts with the pleckstrin
homology (PH) domain of p62, while the XPC C-terminal domain interacts
with the C-terminal helix of XPB (van Eeuwen et al., 2021).

After recruitment by XPC, TFIIH plays two major roles in GG-NER: DNA
unwinding and damage verification, both of which are mainly dependent on
the XPD subunit (\textbf{Figure 2} ). XPD is the major helicase to
unwind the two strands in the NER pathway. While XPB was initially
suggested as another helicase with an opposite polarity to XPD (Fuss \&
Tainer, 2011), other studies show that XPB's ATPase, but not the
helicase function, is required for DNA repair (Coin et al., 2007). This
raises an interesting model that XPB functions as an ATPase for the
initial unwinding and anchoring TFIIH to the DNA strand, resulting in a
helix opening action and engagement of XPD to the DNA. In agreement with
this model, Cryo-EM analysis of the yeast XPC-TFIIH-DNA complex has
provided structural insights into the coordinated action between XPB and
XPC in initiating DNA unwinding (van Eeuwen et al., 2021). The data
shows that XPB binds to the 5' side relative to the damage, whereas XPC
holds the 3' side. XPB uses its ATP-dependent DNA translocase activity
to generate torsion stress and unwind DNA. XPC holds the other side as
an anchor to avoid DNA free rotation. Hence, XPB and XPC function in a
cooperative manner to initiate DNA unwinding. The partially opened DNA
state promoted by XPB and XPC is then delivered to XPD for further
bubble formation and damage verification. These structural data thus
suggest that XPB and XPD act sequentially to promote formation of the
NER bubble structure. Defects in either of XPB or XPD can result in
failure of strand separation around the damage and incomplete repair. In
line with this notion, yeast genetics evidence has shown that truncation
of the C-terminal portion of XPB or point mutations deactivating XPD's
helicase activity leads to extremely high UV sensitivity and low or even
undetectable GG-NER (Duan et al., 2020; van Eeuwen et al., 2021).

XPD also performs a sliding function to verify if a genuine NER damage
is present. This damage verification function is carried out by sliding
a single-stranded DNA (ssDNA) through the central tunnel of XPD protein
formed by an iron-sulfur cluster and an arch domain (Kuper et al.,
2014). This sliding function will stop or be impeded if the DNA has a
bulky lesion and can aid in the translocation of the TFIIH complex to
the location of the damage. The stalling of XPD by a bulky lesion thus
serves as a critical damage verification mechanism before NER initiates
strand excision. Mutations of several amino acids near XPD's central
tunnel abolishes the damage verification function, but does not impact
the DNA helicase activity (Mathieu et al., 2013), suggesting that DNA
unwinding and damage verification are conducted by different functional
domains in XPD. Once the DNA has been opened and the damage verified, it
allows for further proteins of the preincision complex to be recruited
at the lesion site to excise the damaged nucleotides. A critical protein
for the preincision complex assembly is XPA. XPA binds to the 5' end of
the damage and facilitates the recruitments of replication protein A
(RPA) and repair endonuclease XPF-ERCC1 (Sugitani et al., 2016). RPA is
a single-stranded DNA binding protein that binds approximately 30
nucleotides on the undamaged strand. It functions together with XPA as
the central scaffold to ensure proper positioning of the two repair
endonucleases, XPF and XPG, at the site of damage in the DNA (Schärer,
2013).

\emph{2.4. TFIIH Recruitment and Functions in TC-NER}

TC-NER only repairs damage on the transcribed strand of active genes and
is considered more efficient than GG-NER (Hu et al., 2015). A key
difference that distinguishes TC-NER from GG-NER is the presence of
damage-stalled RNA Pol II that serves as the signal for TC-NER
initiation (Lainé \& Egly, 2006). The first protein responding to Pol II
stalling is Cockayne syndrome B (CSB), a SWI2-SNF2 type ATPase (Selby \&
Sancar, 1997). CSB normally binds to DNA upstream of Pol II to promote
transcription elongation (Kokic et al., 2021; Xu et al., 2017). Upon
transcription stalling, CSB quickly moves to Pol II and functions in
recruiting downstream TC-NER proteins, including Cockayne syndrome A
(CSA) (van der Weegen et al., 2020), a component of an E3 ubiquitin
ligase complex (Groisman et al., 2003). CSA can ubiquitylate CSB as well
as the stalled Pol II (Groisman et al., 2006; Nakazawa et al., 2020).
CSA also physically interacts with UV-stimulated scaffold protein A
(UVSSA) (van der Weegen et al., 2020), another important TC-NER protein.

One mechanism for TFIIH recruitment in TC-NER is through its physical
interaction with UVSSA (Okuda et al., 2017; van der Weegen et al., 2020)
(\textbf{Figure 3} ). In this regard, it has been shown that UVSSA also
interacts with the PH domain of TFIIH subunit p62 (Okuda et al., 2017),
in a way similar to the interaction between XPC and TFIIH in GG-NER.
Another mechanism for TFIIH recruitment is via Pol II ubiquitylation.
Recruitment of CSA to the stalled Pol II leads to mono-ubiquitylation of
the largest Pol II subunit, Rpb1, at Lys1268 (Nakazawa et al., 2020;
Tufegd\selectlanguage{polish}ž\selectlanguage{english}i\selectlanguage{polish}ć \selectlanguage{english}Vidakovi\selectlanguage{polish}ć \selectlanguage{english}et al., 2020). Interestingly, Rpb1-Lys1268
ubiquitylation enhances the association of the TFIIH core complex with
the stalled Pol II, and this mechanism appears to involve ubiquitylated
UVSSA at Lys414 (Nakazawa et al., 2020). An additional TC-NER factor
that may participate in TFIIH recruitment to stalled Pol II is ELOF1. It
was suggested that ELOF1, a conserved elongation factor, interacts with
both Pol II and the CRL4\textsuperscript{CSA} E3 ligase, and positions
CRL4\textsuperscript{CSA} for Pol II ubiquitylation at the Rpb1-Lys1268
residue(van der Weegen et al., 2021). As Pol II ubiquitylation increases
Pol II-TFIIH interaction (Nakazawa et al., 2020), ELOF1 likely
facilitates this process by enhancing Pol II ubiquitylation.

Despite TFIIH's roles in DNA unwinding and damage verification in
GG-NER, how TFIIH stimulates TC-NER is much less understood. It is
generally assumed that TFIIH plays identical roles in the two NER
subpathways and there is some evidence supporting this hypothesis. For
example, it has been shown that a helicase-dead XPD mutant abolishes
both subpathways in yeast (Duan et al., 2020). However, it is also
important to note that TC-NER significantly differs from GG-NER in that
the two DNA strands are pre-melted in a transcription bubble by RNA Pol
II (\textbf{Figure 3} ). When RNA Pol II is stalled by the damage, it is
conceivable that TFIIH may not need to unwind the two strands from
scratch, instead, it is possible that TFIIH may just need to extend the
transcription bubble to \textasciitilde{}30 nt for the formation of NER
pre-incision complex. Consistent with this notion, clinical data have
shown that mutations in XPD, the major helicase responsible for DNA
unwinding, are mainly associated with the skin cancer-prone disease,
xeroderma pigmentosum (XP), which is generally considered to be caused
by GG-NER defects (Coin et al., 1998; Lehmann, 2001). Only a small
number of XPD mutations are associated with the severe symptom of XP in
combination with the TC-NER disease, Cockayne syndrome (CS) (Lehmann,
2001; Rapin et al., 2000).

One possible explanation for the clinical observations is that the XPD
mutations in most patients may retain partial helicase activity that is
strong enough to increase the bubble size using the pre-melted DNA in
TC-NER. However, the attenuated helicase activity may not be enough for
generating a repair bubble in GG-NER on an almost fully annealed DNA
double helix. More detailed DNA repair studies in different XPD mutant
cells (e.g., XP-only or XP plus CS) may help us understand the
underlying mechanism for different XPD symptoms and delineate the exact
roles of TFIIH in the two subpathways. Furthermore, to what extent XPD's
damage verification function is required for TC-NER is also up for
debate; because RNA Pol II stalling should already be a stringent
mechanism to verify the presence of DNA damage. Whether TC-NER needs
both Pol II stalling and TFIIH to verify damage presence needs more
experimental analysis.

It is also still not fully understood if RNA Pol II is evicted from the
DNA to make way for the TFIIH repair complex, along with other NER
factors, or if it simply backtracks along the DNA in the transcription
bubble. There are a number of theories about what could be happening,
but each raises its own questions. If RNA Pol II dissociates from the
DNA, how is it recruited back? Does it retain the transcript in
progress, or does it need to start at the promoter region again? If RNA
Pol II is backtracked, what is the mechanism promoting Pol II
backtracking along the DNA? Considering TFIIH's DNA helicase function,
future studies should also test a potential role for TFIIH in aiding Pol
II dissociation from DNA or backtracking in TC-NER.

\emph{2.5. TFIIH functions as a ubiquitin ligase in DNA damage repair}

The TFIIH complex contains E3 ubiquitin (Ub) ligase activity, which
primarily resides within the p44 subunit (Ssl1 in yeast) in the ring
finger domain (RNF) (Takagi et al., 2005). The p44 subunit is known for
its role in the enhancement of XPD helicase activity in the NER pathway,
but this E3 Ub ligase activity is interesting in the context of TFIIH's
role in both NER and transcription. It is noted that RNA Pol II is
ubiquitinated during transcription and during repair; however, the
evidence suggests that this is not the role for p44's E3 Ub Ligase. It
is suggested that Ssl1-mediated ubiquitin ligase function targets
unknown transcription activator proteins to mediate the DNA damage
response, as mutations introduced in this RNF domain in Ssl1 leads to a
reduction in transcription of DNA repair genes in response to exposure
to DNA damage (Takagi et al., 2005). Whether the ubiquitylation-mediated
transcription response directly affects DNA repair has not been
analyzed.

\textbf{3. TFIIH Mutations, Diseases/Disorders and Potential Therapeutic
Opportunities}

Due to the crucial role of TFIIH in NER, germline mutations in TFIIH
subunits have been linked with human disorders, including XP, XP in
combination with CS (XP/CS), and Trichothiodystrophy (TTD) (Coin et al.,
1998; Lehmann, 2001; Rapin et al., 2000). Most of the pathogenic TFIIH
germline mutations occur in the XPD subunit. Of note, many of the
mutations within the XPD protein that lead to the XP, XP/CS, and TTD
disease states are found towards the end of the protein (\textbf{Table
1} ), in the final helicase residues and the p44 binding domain
(Lehmann, 2001). Furthermore, somatic mutations in TFIIH, particularly
mutations in the XPD subunit, have been widely observed in human cancers
(Kim et al., 2016). Somatic mutations in XPD can presumably increase
genome instability and promote tumorigenesis. On the other hand,
mutations in XPD represent potential vulnerability of tumor cells that
can be targeted by treatment with DNA damaging agents, such as
platinum-based chemotherapy, thus providing an important opportunity to
treat these tumors (Q. Li et al., 2019).

\emph{3.1. TFIIH and Xeroderma Pigmentosum (XP)}

XP is an autosomal recessive disorder, characterized by photosensitivity
and the predisposition to skin cancer. There are many other factors,
such as thinning hair and skin, freckles, effect on eye, and even when
sunscreen is used, the likelihood of cancer is still very high from a
young age. Of the affected individuals with XP, approximately 25\% could
develop neurological affects, such as acquired microcephaly, hearing
loss, cognitive impairment, impacted central nervous system and
neurodegeneration (Kraemer et al., 2022). This has come to be to known
as XP neurological disease (Y. Krasikova et al., 2021). XP can arise
from mutations occurring in several factors in the NER pathway, with
varying clinical outcomes. These complementation groups vary in severity
and rate of occurrence within the population; however, mutations within
XPA, XPC, and XPD are most common and account for more than 70\% of all
XP cases (Cleaver, 2008; Martens et al., 2021).

Most XP-associated mutations in TFIIH are found in the XPD subunit,
particularly at arginine 683 (R683) in the C-terminal domain of XPD
(Taylor et al., 1997). This residue is close to one of XPD's DNA
helicase motifs and its mutation attenuates the helicase
activity\emph{in vitro} (Coin et al., 2007). A number of other
XP-associated mutations have also been found, mainly in the C-terminal
domain of XPD (\textbf{Table 1} ). It is generally believed that XP
symptoms are correlated with defects in the GG-NER subpathway (Fousteri
\& Mullenders, 2008; Laat et al., 1999; Martens et al., 2021). The
global repair deficiency increases UV mutations and higher risk of
carcinogenesis in exposed skins cells. Hence, the clinical observations
imply that the XP-associated mutations in the XPD gene may selectively
block the GG-NER subpathway, but have less severe effect on TC-NER.

Mutations in other TFIIH subunits can also lead to XP. For example,
mutations in XPB and p8 subunits have been shown to cause XP symptoms
(Rimel \& Taatjes, 2018; Singh et al., 2015).

\emph{3.2. TFIIH and XP/CS Symptoms}

Cockayne Syndrome (CS) is also an autosomal recessive disorder,
characterized by neurodegeneration and premature aging. Other CS
phenotypes include cerebellar atrophy and demyelination. There are
multiple proteins within the NER pathway that lead to CS, particularly
for the two initiation factors in TC-NER, CSB and CSA. Several mutations
in CSB or CSA have been shown to cause CS, but they do not lead to XP,
suggesting CS is specifically related to defective TC-NER activity
(Fousteri \& Mullenders, 2008; Rapin et al., 2000). The mechanism of CS
is especially interesting and puzzling, because UV damage does not
directly occur in the brain and it is unknown to what extent failure to
repair bulky lesions in active genes in neuronal cells contributes to
the onset of CS. Alternatively, previous studies suggest that CS may be
caused by defective repair of oxidative damage and/or improper
expression of genes related to neuron development (Y. Wang et al.,
2014). Interestingly, a small number of mutations in the XPD gene are
associated with XP combined with CS (XP/CS) (Lehmann, 2001; Rapin et
al., 2000). If TC-NER deficiency plays a causative role in CS, these
XP/CS mutations in XPD may cause deficiency in both subpathways in NER.
The identified XP/CS mutations are located either within the conserved
helicase motif, or in the p44-interacting domain (Lehmann, 2001). Why
these mutations cause both XP and CS symptoms whereas the majority of
other XPD mutations lead to XP disease, but no CS, remains unclear.

\emph{3.3. TFIIH and Trichothiodystrophy (TTD)}

Trichothiodystrophy (TTD) is another autosomal recessive disorder,
caused by mutations within the NER proteins, including TFIIH. TTD is
characterized by Sulphur-deficient brittle hair, dry and scaly skin
(ichthyosis), congenital cataracts, poor coordination, and skeletal
abnormalities (Lehmann, 2001; Stefanini, 2013; Taylor et al., 1997).
Despite sensitivity to sunlight, there are no reports of skin cancer or
any similarities to the XP group. TTD is considered to be a
transcription syndrome. However, it has been noted that TTD does have
some repair deficiencies at certain mutation sites, but they are very
heterogenous between patients in the severity of repair deficiency
(Lehmann, 2001).

There is evidence to support the theory that mutations occurring in
different proteins can destabilize the TFIIH complex, inhibiting parts
of the function that occur during transcription (Botta et al., 2002;
Stefanini, 2013). This inhibition will then cause deficiency in
pre-initiation complex (PIC) assembly and the ability for the DNA to be
opened for transcription initiation. Different mutations may have the
potential to behave differently, depending on where the mutation is
located within the protein, which protein in TFIIH is affected, and how
this mutation effects the interactions between the individual subunits
of the TFIIH complex (Coin et al., 1998; Singh et al., 2015; Taylor et
al., 1997). As shown in \textbf{Table 1} , mutations in XPD, XPB, and p8
subunits have been implicated in TTD.

\emph{3.4. Effects of Defective TFIIH on Carcinogenesis and Cancer
Treatment}

As TFIIH plays a critical role in maintaining genome stability, cells
with defective TFIIH are more likely to have high genome instability,
which may further elevate cancer risk. Indeed, somatic mutations in the
XPD gene, which is also named ERCC2, have been widely observed in
tumors, such as bladder and urothelial cancers (Kim et al., 2016).
Tumors of the urothelial tract and bladder are associated with exposure
to tobacco and other DNA damaging chemicals that induce bulky lesions
(Freedman et al., 2011; Ploeg et al., 2009). Lack of TFIIH may render
the exposed cells more vulnerable to these damaging agents, thereby
promoting genome instability and tumor growth. Additionally, it has been
shown that somatic mutations in XPD are associated with a distinct
genomic signature in urothelial tumors, signature 5*, which closely
resembles COSMIC signature 5 (Kim et al., 2016). There is also evidence
indicating a correlation between signature 5* and smoking (Kim et al.,
2016), which suggests that low repair of tobacco-induced DNA damage in
XPD-mutated cancer cells may drive this unique mutation signature. On
the other hand, somatic mutations in XPD also represent an intrinsic
vulnerability of the tumor cells to various therapies. This idea has
been tested in bladder cancer, in which XPD somatic mutations are
frequently found. The published data shows that many clinically observed
XPD mutations enhance sensitivity to cisplatin in cancer cell lines and
mouse xenograft models (Q. Li et al., 2019).

Another common mutation site is in the CDK7 subunit of the CAK complex
of TFIIH. Mutations in this subunit are associated with triple negative
breast cancer, peripheral T-cell lymphomas, and ovarian cancer.
Preclinical models have shown that the use of CDK7 inhibitors reduces
drug resistance in human cells and mouse models (Rimel \& Taatjes,
2018).

\textbf{4. Conclusions}

DNA damage can occur throughout life; therefore, it is fundamental for
DNA repair to occur to preserve the genetic material encoded. NER is one
of the repair pathways, and it is responsible for the removal and repair
of bulky lesions within the DNA. NER has two subpathways, GG-NER and
TC-NER, both of which play an important role and require the recruitment
and activity of the TFIIH complex. TFIIH is important for damage
verification, unwinding of the DNA, and holding open the excision bubble
for the other NER proteins to function. When defects occur in the
proteins in TFIIH and the proteins throughout the rest of the pathway,
genetic disorders will occur with varying clinical phenotypes and
severity. Proteins within the TFIIH complex also provide therapeutic
targets in cancer chemotherapeutic treatments to different cancers and
understanding mechanisms of resistance within them as well.

However, despite the extensive research and knowledge on the NER pathway
and the TFIIH complex, there are still many knowledge gaps regarding the
detailed functions of TFIIH in NER. For example, how do XPB and XPD
coordinate to open the two DNA strands? What exact roles does TFIIH play
in TC-NER? Why germline mutations in XPD, some of them occur in residues
close to each other (e.g., Arg601 and Gly602)(Lehmann, 2001), exhibit
significantly different clinical phenotypes? More research is needed to
further elucidate the mechanisms and the role of each of the individual
subunits of the TFIIH complex in both transcription and the NER pathway.

\textbf{Acknowledgements}

DNA repair studies related to this review are supported by the National
Cancer Institute (NCI) grant R01CA273458 (to P.M.), UNM Comprehensive
Cancer Center Support Grant NCI P30CA118100, and UNM Analytical and
Translational Genomics Shared Resource.



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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1} : The human TFIIH complex. Eight of the ten TFIIH
subunits are recognizable in this structure. The structural model was
made with PyMOL using the published data (PDB accession number: 5OF4).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2} : Recruitment and functions of TFIIH in GG-NER. XPC
binds to the damage site first. The interaction between XPC and TFIIH
subunits p62 and XPB leads to the recruitment of TFIIH. XPA removes the
CAK kinase module, which activates the helicase function of the TFIIH
core complex to conduct DNA unwinding and damage verification.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3} : Recruitment and potential functions of TFIIH in
TC-NER. The p62 subunit of TFIIH physically interacts with UVSSA and the
interaction facilitates TFIIH recruitment to the damage-stalled RNA Pol
II. Pol II ubiquitylation at Lys1268 enhances binding of TFIIH to Pol
II. As DNA around the lesion is melted by RNA Pol II, the recruited
TFIIH potentially extends the transcription bubble to generate a
full-sized repair bubble. Similar to GG-NER, TFIIH may also verify the
presence of a bulky lesion. However, it is unclear to what extent TC-NER
requires TFIIH's damage verification function, because RNA Pol II
stalling may play a redundant role. Another potential role for TFIIH is
to help Pol II backtracking or displacement.

\textbf{Table 1: TFIIH mutations and human disorders}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Genes}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Mutations}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Symptoms}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
G47R\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP (Lehmann, 2001)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
T76A\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
D234N\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R511Q\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
S541R\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Y542C\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R601L\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R601W\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R666W\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
D683W\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R683Q\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Q726 Stop\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
G602D\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP/CS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
G675R\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP/CS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R112H\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
C259Y\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R487G\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R592P\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
A594P\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R658H\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R658C\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
C663R\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
D673G\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
G713R\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R722W\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
A725P\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPD\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Frameshift 730\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPB\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
T119P\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD (Weeda, 1997)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
XPB\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
F99S\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
XP (Oh, 2006) XP/CS (Singh, 2015)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XPB\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Q739insX42 (alteration of the C-terminal 41 amino acids)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
XP/CS (Oh, 2006)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
p8\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
L21P\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD (Giglia-Mari, 2004)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
p8\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
R56 Stop\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
p8\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
M1T (no start)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
TTD\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

