Baranes-Bachar, KerenLevy-Barda, AdvaOehler, JudithReid, Dylan ASoria-Bretones, IsabelVoss, Ty CChung, DudleyPark, YoonLiu, ChaoYoon, Jong-BokLi, WeiDellaire, GrahamMisteli, TomHuertas, PabloRothenberg, EliRamadan, KristijanZiv, YaelShiloh, Yosef2023-01-252023-01-252018http://hdl.handle.net/10668/12204Double-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.enDNA damageUBE4Adouble-strand breaksgenome stabilityubiquitinBRCA1 ProteinCarrier ProteinsDNA Breaks, Double-StrandedDNA-Binding ProteinsHeLa CellsHistone ChaperonesHumansNuclear ProteinsRecombinational DNA RepairUbiquitin-Protein LigasesUbiquitinationUbiquitinsresearch article29499138open access10.1016/j.molcel.2018.02.0021097-4164PMC6265044http://www.cell.com/article/S109727651830100X/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265044/pdf