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

• Published in: Nature communications Vol. 9; no. 1; pp. 3233 - 13
• Main Authors: Chen, Qian, Kassab, Muzaffer Ahmad, Dantzer, Françoise, Yu, Xiaochun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 13/89; 42/41; 631/337/458/2389; 631/45/607/1159; 82/29; 82/58; 96/63; Adenosine diphosphate; ADP-ribosylation; Animals; Biological activity; Cell Line, Tumor; Chain branching; Chemical synthesis; Chromatin remodeling; Damage; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA-(Apurinic or Apyrimidinic Site) Lyase - chemistry; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Enzymatic activity; Fibroblasts - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Life Sciences; Mice; multidisciplinary; N-Terminus; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly ADP Ribosylation; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - chemistry; Poly(ADP-ribose) Polymerases - metabolism; Poly-ADP-Ribose Binding Proteins - chemistry; Poly-ADP-Ribose Binding Proteins - metabolism; Polymerization; Repair; Ribose; Ribosylation; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05588-5

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. PARP1 and PARP2 of the PARP family enzymes are involved in DNA damage response. Here the authors report PARP2 activation mechanisms and its role in the formation of branched poly(ADP-ribose) chains in response to DNA damage.