C8orf33 dictates DNA double-strand break repair choice by modulating KAT8-mediated H4K16 acetylation

Consequently, C8orf33 inhibits DNA end resection and counteracts the recruitment of HR factors, BRCA1 and RAD51, to DSB sites. Mechanistically, chromatin profiling analysis reveals that C8orf33 antagonizes the chromatin association of KAT8 acetyltransferase at DSB sites leading to reduced histone 4 lysine 16 acetylation (H4K16ac) levels. Accordingly, the loss of C8orf33 enhances KAT8 chromatin binding that increases H4K16ac levels.

This promotes the recruitment of HR factors while suppressing the accumulation of NHEJ factors at DSB sites, thereby favoring HR over NHEJ. Additionally, we demonstrate that the elevated HR activity in C8orf33-deficient cells causes genomic instability, as evidenced by accelerated loss of ribosomal DNA repeats and increases cell death. Collectively, our findings establish C8orf33 as a critical regulator of DSB repair pathway choice, safeguarding genomic integrity.