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\begin{document}

\title{Regulation of Non-Canonical Proteins Encoded by Small Open Reading
Frames via the Nonsense-Mediated Decay Pathway}



\author[1]{PARTHIBAN PERIASAMY}%
\author[1]{Craig Joseph}%
\author[2]{Adrian Campos}%
\author[2]{Sureka Rajandran}%
\author[2]{Christopher Batho}%
\author[2]{James Hudson}%
\author[2]{Haran Sivakumaran}%
\author[2]{Hitesh Kore}%
\author[2]{Keshava Datta}%
\author[1]{Joe Yeong}%
\author[2]{Harsha Gowda}%
\affil[1]{Institute of Molecular and Cell Biology}%
\affil[2]{QIMR Berghofer Medical Research Institute}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\begin{abstract}
Immunotherapy harnesses neoantigens encoded within the human genome, but
their therapeutic potential is hampered by low expression, which may be
controlled by the Nonsense-Mediated Decay (NMD) pathway. This study
investigates the impact of UPF1-knockdown on the expression of
non-canonical/mutant proteins, employing proteogenomic to explore UPF1
role within the NMD pathway. Additionally, we conducted a comprehensive
pan-cancer analysis of UPF1 expression and evaluated UPF1 expression in
Triple-Negative Breast Cancer (TNBC) tissue in-vivo. Our findings reveal
that UPF1-knockdown leads to increased transcription of
non-canonical/mutant proteins, particularly those originating from
retained-introns, pseudogenes, long non-coding RNAs, and unannotated
transcript biotypes. Moreover, our analysis demonstrates elevated UPF1
expression in various cancer types, with notably heightened protein
levels in patient-derived TNBC tumours compared to adjacent tissues.
This study elucidates UPF1 role in mitigating transcriptional noise by
degrading transcripts encoding non-canonical/mutant proteins.
Intriguingly, we observe an upregulation of the NMD pathway in cancer,
potentially acting as a ``neoantigen-masking'' mechanism that suppresses
non-canonical/mutant protein expression. Targeting this mechanism may
reveal a new spectrum of neoantigens accessible to the antigen
presentation pathway. Our novel findings provide a strong foundation for
the development of therapeutic strategies aimed at targeting UPF1 or
modulating the NMD pathway.%
\end{abstract}%



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