C8orf33: A novel regulator of DNA double strand break repair choice
Living organisms are continuously exposed to exogenous and endogenous DNA-damaging agents that form DNA lesions. One of the most cytotoxic types of DNA lesions is double strand break (DSB) and its defective repair triggers genomic instability and carcinogenesis. DSBs are repaired through two main repair pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). While HR ensures accurate repair, NHEJ is a rapid but mostly mutagenic repair pathway. Maintaining the balance between HR and NHEJ is crucial for preserving genomic stability. Consequently, there is increasing interest in elucidating the molecular mechanisms that govern DSB repair pathway selection. Here, we identify the uncharacterized C8orf33 protein as a novel regulator of DSB repair choice. Our data reveal that C8orf33 is a nuclear protein localized predominantly to the nucleolus and accumulates at DSB sites within both nuclear and nucleolar regions. We demonstrate that C8orf33 promotes NHEJ and suppresses HR repair of DSBs. Mechanistically, we show that C8orf33 alters the epigenetic mark histone 4 lysine 16 acetylation (H4K16ac), which controls the recruitment of NHEJ and HR factors to DSB sites. Accordingly, C8orf33 deficiency elevates HR repair which results in genomic instability, as evidenced by the loss of nucleolar DNA content and increased cell lethality. Collectively, our findings establish C8orf33 as a critical regulator of DSB repair pathway choice, safeguarding genomic integrity.
