Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks

摘要: The occurrence of a double-strand break in DNA activates complex series events that recruit to the many proteins involved its repair. A number these are modified by addition small protein, SUMO; this modification is performed SUMO ligases. In work, Jackson and colleagues show two such ligases, PIAS1 PIAS4, add various SUMOs onto repair at breaks. PIAS ligases recruited via their SAP domains, activity required for effective SUMOylation PIAS4 also necessary further certain factors ubiquitin, somewhat larger protein adduct related SUMO. successive ubiquitylation regulates targeting to, of, Following formation (DSB), cells activate DNA-damage response lesion. Some attachment ubiquitin-related modifier (SUMO). Here, SUMO1, SUMO2 SUMO3 shown accumulate DSB sites mammalian cells. SUMO1 SUMO2/3 accrual requires E3 ligase enzymes PIAS1, which promote breaks (DSBs) highly cytotoxic lesions generated ionizing radiation DNA-damaging chemicals. formation, (DDR) kinases ATM, ATR DNA-PK (also known as PRKDC). These then trigger histone H2AX H2AFX) phosphorylation accumulation MDC1, 53BP1 TP53BP1), BRCA1, CtIP RBBP8), RNF8 RNF168/RIDDLIN into radiation-induced foci (IRIF) amplify signalling repair1,2. Attachment (SUMO) target controls diverse cellular functions3,4,5,6. we cells, with requiring PIAS1. We establish damage mechanisms needed productive association 53BP1, BRCA1 RNF168 regions. Furthermore, confer resistance. Finally, ubiquitin-adduct mediated RNF8, damage7,8,9,10,11. findings thus identify components DDR reveal how recruitment controlled coordinated ubiquitylation.