C8orf33: A novel regulator of DNA double-strand break repair pathway choice

Exogenous and endogenous mutagens attack our genome on a regular basis, causing various types of DNA lesions. Cells have evolved sophisticated DNA damage response (DDR) mechanisms to repair these lesions and preserve genomic stability. Double-strand breaks (DSBs) are the most cytotoxic type of DNA lesions, and its defective repair can trigger genomic instability and carcinogenesis. Eukaryotic cells employ two main DSB repair pathways: homologous recombination (HR) an error free process restricted to late S/G2 phase, and the error prone non-homologous end joining (NHEJ) that occurs at G1, S and G2 phases. Increasing number of factors that regulate DSB repair pathway choice are being identified. Here, we identified a previously uncharacterized gene, C8orf33, as a novel regulator of DSB repair pathway choice. We showed that C8orf33 encodes for a nuclear protein and is enriched at the nucleolus. Remarkably, C8orf33 is rapidly recruited to DSB sites in a PARP1-dependent manner, and its depletion promotes HR and counteracts NHEJ. Mechanistically, we demonstrated that C8orf33 deficiency leads to elevated levels of DNA-end resection, which underpins the recruitment of HR factors, RPA2, BRCA1 and RAD51 to DSB sites. Notably, C8orf33 is misregulated in various types of human malignancies including hepatocellular carcinoma. Collectively, our results provide a potential link between C8orf33 misregulation in cancer and its role in DNA repair. They are also likely to pave the way for new avenues of therapy for tumors harboring C8orf33 mutations.