PARP2 mediates branched poly ADP-ribosylation in response to DNA damage

被引:122
作者
Chen, Qian [1 ]
Kassab, Muzaffer Ahmad [1 ]
Dantzer, Francoise [2 ]
Yu, Xiaochun [1 ]
机构
[1] City Hope Med Ctr, Beckman Res Inst, Dept Canc Genet & Epigenet, Duarte, CA 91010 USA
[2] Strasbourg Univ, CNRS, Ecole Super Biotechnol Strasbourg, Biotechnol & Cell Signaling,UMR7242, BP10413, F-67412 Illkirch Graffenstaden, France
基金
美国国家卫生研究院;
关键词
STRAND BREAK REPAIR; POLY(ADP-RIBOSE) POLYMERASE-2; STRUCTURAL BASIS; DOMAIN; RECOGNITION; RIBOSE; APLF; SITES; UBIQUITINATION; IDENTIFICATION;
D O I
10.1038/s41467-018-05588-5
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Poly(ADP-ribosyl) ation (PARylation) is a posttranslational modification involved in multiple biological processes, including DNA damage repair. This modification is catalyzed by poly (ADP-ribose) polymerase (PARP) family of enzymes. PARylation is composed of both linear and branched polymers of poly(ADP-ribose) (PAR). However, the biochemical mechanism of polymerization and biological functions of branched PAR chains are elusive. Here we show that PARP2 is preferentially activated by PAR and subsequently catalyzes branched PAR chain synthesis. Notably, the direct binding to PAR by the N-terminus of PARP2 promotes the enzymatic activity of PARP2 toward the branched PAR chain synthesis. Moreover, the PBZ domain of APLF recognizes the branched PAR chain and regulates chromatin remodeling to DNA damage response. This unique feature of PAR-dependent PARP2 activation and subsequent PARylation mediates the participation of PARP2 in DNA damage repair. Thus, our results reveal an important molecular mechanism of branched PAR synthesis and a key biological function of branched PARylation.
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页数:13
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