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Regulation of Non-Canonical Proteins Encoded by Small Open Reading Frames via the Nonsense-Mediated Decay Pathway
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  • PARTHIBAN PERIASAMY,
  • Craig Joseph,
  • Adrian Campos,
  • Sureka Rajandran,
  • Christopher Batho,
  • James Hudson,
  • Haran Sivakumaran,
  • Hitesh Kore,
  • Keshava Datta,
  • Joe Yeong,
  • Harsha Gowda
PARTHIBAN PERIASAMY
Institute of Molecular and Cell Biology

Corresponding Author:[email protected]

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Craig Joseph
Institute of Molecular and Cell Biology
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Adrian Campos
QIMR Berghofer Medical Research Institute
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Sureka Rajandran
QIMR Berghofer Medical Research Institute
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Christopher Batho
QIMR Berghofer Medical Research Institute
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James Hudson
QIMR Berghofer Medical Research Institute
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Haran Sivakumaran
QIMR Berghofer Medical Research Institute
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Hitesh Kore
QIMR Berghofer Medical Research Institute
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Keshava Datta
QIMR Berghofer Medical Research Institute
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Joe Yeong
Institute of Molecular and Cell Biology
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Harsha Gowda
QIMR Berghofer Medical Research Institute
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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.
19 Sep 2023Submitted to PROTEOMICS
19 Sep 2023Submission Checks Completed
19 Sep 2023Assigned to Editor
19 Sep 2023Review(s) Completed, Editorial Evaluation Pending
26 Sep 2023Reviewer(s) Assigned
06 Nov 2023Editorial Decision: Revise Minor
24 Jan 2024Review(s) Completed, Editorial Evaluation Pending
28 Jan 20242nd Revision Received
01 Feb 2024Editorial Decision: Accept