Abstract 2760: Does a short open reading frame (sORF)-encoded protein participate in DNA repair

Abstract

Non-homologous end joining (NHEJ) is one of the major mechanisms for rejoining of DNA double-strand breaks. Knowledge of the molecular mechanism of NHEJ will help us to understand how this process preserves genome integrity, and how NHEJ errors cause chromosomal rearrangements that lead to cancer. Several critical participants in the NHEJ pathway have been identified and some mechanistic steps have been characterized. At present, a significant gap in our understanding of NHEJ is how NHEJ factors assemble at DSBs. It is plausible that additional, as yet unidentified, factors contribute to NHEJ assembly. We have biochemical and biological data implicating a short open reading frame (sORF)-encoded protein in NHEJ. sORFs are found in all genomes. Ribosome profiling, mass spectroscopy and RNA sequencing have predicted the existence of numerous sORF-encoded proteins of <100 amino acids in size. While the functional significance of the majority of these small proteins is not clear, we recently discovered that a 69 amino acid protein encoded by chromosome 7 open-reading frame 49 (C7orf49) interacts with critical NHEJ factors in human cells, and stimulates NHEJ in cell-free extracts. Treatment of cells with the DSB-inducing agent etoposide increased C7orf49 expression and nuclear localization, and knockdown of C7orf49 sensitized cells to etoposide. C7orf49-deficient cells exhibited a mild proliferation defect and increased sensitivity to etoposide. Our data suggest that this small protein may play an important role in double-strand beak repair by NHEJ and highlights the potential biological relevance of sORF-encoded proteins in the DNA damage response and in DNA repair. Citation Format: Les Hanakahi, Matthew Summerlin, Yi-Chia Tang, Jinho Heo. Does a short open reading frame (sORF)-encoded protein participate in DNA repair. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2760.