Pancsa, Rita and Andreev, Dmitry E. and Dean, Kellie (2025) The implication of non-AUG-initiated N-terminally extended proteoforms in cancer. RNA BIOLOGY, 22 (1). pp. 1-18. ISSN 1547-6286
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Abstract
Dysregulated translation is a hallmark of cancer, and recent genome-wide studies in tumour cells have uncovered widespread translation of non-canonical reading frames that often initiate at non-AUG codons. If an upstream non-canonical start site is located within a frame with an annotated coding sequence (CDS), such translation events can lead to the production of proteoforms with altered N-termini (PANTs). Certain examples of PANTs from oncogenes (e.g. c-MYC) and tumour suppressors (e.g. PTEN) have been previously linked to cancer. We have performed a systematic computational analysis on recently identified non-AUG initiation-derived N-terminal extensions of cancer-associated proteins, and we discuss how these extended proteoforms may acquire new oncogenic properties. We identified a loss of stability for the N-terminally extended proteoforms of oncogenes TCF-4 and SOX2. Furthermore, we discovered likely functional short linear motifs within the N-terminal extensions of oncogenes and tumour suppressors (SOX2, SUFU, SFPQ, TOP1 and SPEN/SHARP) that could provide an explanation for previously described functionalities or interactions of the proteins. In all, we identify novel cases where PANTs likely show different localization, functions, partner binding or turnover rates compared to the annotated proteoforms. Therefore, we propose that alterations in the stringency of translation initiation, often seen under conditions of cellular stress, may result in reprogramming of translation to generate novel PANTs that influence cancer progression.
| Item Type: | Article |
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| Additional Information: | Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow, Russian Federation Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland Export Date: 19 May 2025; Cited By: 0 |
| Uncontrolled Keywords: | Humans; metabolism; GENETICS; human; Chemistry; gene expression regulation; Protein Biosynthesis; Gene Expression Regulation, Neoplastic; Oncogenes; Neoplasms; protein synthesis; neoplasm; OPEN READING FRAMES; Computational Biology; Oncogene; open reading frame; SOXB1 Transcription Factors; bioinformatics; TRANSLATION INITIATION; start codon; start codon; Codon, Initiator; procedures; Short linear motifs; transcription factor Sox; N-terminal extension; non-AUG initiation; alternative translation start site; proteoforms with altered N-termini; |
| Subjects: | Q Science / természettudomány > QR Microbiology / mikrobiológia R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 16 Sep 2025 11:43 |
| Last Modified: | 16 Sep 2025 11:43 |
| URI: | https://real.mtak.hu/id/eprint/224317 |
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