Dna Damage RESPONSE DNA Takes a Break with SUMO

RESEARCH HIGHLIGHTS DNA DAMAGE RESPONSE DNA takes a break with SUMO During the DNA damage response Both groups show that UBC9, The ubiquitylation of histones (DDR), repair proteins such as the SUMO1, SUMO2 and SUMO3 accu- H2A and H2AX at sites of DNA dam- the E3 SUMO E3 ubiquitin ligase BRCA1 accu- mulate at DSBs in mammalian cells age, which mediates the recruitment ligases PIAS1 mulate at DNA double-stranded in a PIAS1- and PIAS4-dependent of further repair proteins, is mediated breaks (DSBs), and ubiquitylation manner. Furthermore, depletion of by the E3 ubiquitin ligases BRCA1, and PIAS4 at these sites helps recruit further PIAS1 and PIAS4 causes a decrease RNF8 and RNF168. Galanty et al. have an repair proteins. Small ubiquitin- in DSB repair by homologous show that depletion of PIAS4 reduces important related modifier (SUMO) — which recombination and non-homologous histone H2A ubiquitylation at DSBs role in the is attached to proteins by a pathway end joining, indicating a functional and impairs the recruitment of involving the E1 enzyme SAE1, the role for these E3 SUMO ligases in RNF168 to these sites of damage. mammalian E2 enzyme UBC9 (also known as DNA repair. Morris et al. show that depletion of DDR pathway UBE21) and an E3 ligase (such as So, what is the function of SUMO PIAS1, PIAS4 or BRCA1 reduces PIAS1 and PIAS4) — has also been and PIAS proteins at DSBs and how the level of BRCA1-dependent implicated in the DDR, but its role do they contribute to DNA repair? ubiquitylation at DSBs, and that was unclear. Yaron Galanty et al. During the DDR, histone H2AX is PIAS1 and PIAS4 are required for and Joanna Morris et al. now report phosphorylated in the chromatin the accumulation of RNF168 and that PIAS1 and PIAS4 promote surrounding DSBs, which results ubiquitin conjugates generated by DNA repair and are required for in the recruitment of repair factors, RNF168 at damage sites. These data BRCA1 E3 ubiquitin ligase activity such as tumour suppressor p53- provide further evidence that SUMO at DSBs. binding protein 1 (TP53BP1) and the and ubiquitin function together at E3 ubiquitin ligases BRCA1, RNF8 DSBs to promote DNA repair. and RNF168, to damaged DNA. Collectively, these studies reveal Galanty et al. show that PIAS1 and that the E3 SUMO ligases PIAS1 and PIAS4 are recruited to DSBs by PIAS4 have an important role in the their SAP domains and mediate the mammalian DDR pathway by regu- association of TP53BP1, BRCA1 lating the recruitment of key DNA and RNF168 with damage sites. repair proteins to DSBs, the sumoyla- They also find that TP53BP1 and tion of TP53BP1 and BRCA1, and the BRCA1 are sumoylated in response E3 ubiquitin ligase activity of BRCA1. to ionizing radiation, and that these Katharine H. Wrighton sumoylation events are promoted Associate Editor, by PIAS1 and PIAS4. Morris et al. Nature Reviews Molecular Cell Biology independently show that PIAS1 and PIAS4 promote BRCA1 sumoy- ORIGINAL RESEARCH PAPERS Galanty, Y. et al. lation at sites of DNA damage in Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand hydroxyurea-treated cells, and that breaks. Nature 462, 935–939 (2009) | Morris, J. R. sumoylation of BRCA1 in vitro et al. The SUMO modification pathway is involved increases its E3 ubiquitin ligase in the BRCA1 response to genotoxic stress. Nature 462, 886–890 (2009) activity. NATURE REVIEWS | CANCER VOLUME 10 | FEBRUARY 2010 © 2010 Macmillan Publishers Limited. All rights reserved.

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