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Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair.

Original publication




Journal article


Mol Cell

Publication Date





866 - 878.e7


DNA damage, UBE4A, double-strand breaks, genome stability, ubiquitin, BRCA1 Protein, Carrier Proteins, DNA Breaks, Double-Stranded, HeLa Cells, Humans, Nuclear Proteins, Recombinational DNA Repair, Ubiquitin-Protein Ligases, Ubiquitination, Ubiquitins