A Novel Reciprocal Crosstalk between RNF168 and PARP1 to Regulate DNA Repair Processes
Jae Jin Kim1,2,3,5, Seo Yun Lee1,2,3,5, Soyeon Kim1,2,3, Jee Min Chung1,2,3, Mira Kwon1,2,3, Jung Hyun Yoon1,2,3,
Sangwook Park1,2,3, Yiseul Hwang1,2,3, Dongsun Park1,2,3, Jong-Soo Lee1,4,*, and Ho Chul Kang1,2,3,*
1Genomic Instability Research Center, Ajou University School of Medicine, Suwon 16499, Korea, 2Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea, 3Department of Biomedical Sciences, The Graduate School, Ajou University School of Medicine, Suwon 16499, Korea, 4Department of Life Sciences, College of Natural Sciences, Ajou University, Suwon 16499, Korea, 5These authors contributed equally to this work.
*Correspondence: hckang@ajou.ac.kr (HCK); jsjlee@ajou.ac.kr (JSL)
Received February 22, 2018; Revised June 25, 2018; Accepted June 26, 2018.; Published online July 24, 2018.
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ABSTRACT
Emerging evidence has suggested that cellular crosstalk between RNF168 and poly(ADP-ribose) polymerase 1 (PARP1) contributes to the precise control of the DNA damage response (DDR). However, the direct and reciprocal functional link between them remains unclear. In this report, we identified that RNF168 ubiquitinates PARP1 via direct interaction and accelerates PARP1 degradation in the presence of poly (ADP-ribose) (PAR) chains, metabolites of activated PARP1. Through mass spectrometric analysis, we revealed that RNF168 ubiquitinated multiple lysine residues on PARP1 via K48-linked ubiquitin chain formation. Consistent with this, micro-irradiation-induced PARP1 accumulation at damaged chromatin was significantly increased by knockdown of endogenous RNF168. In addition, it was confirmed that abnormal changes of HR and HNEJ due to knockdown of RNF168 were restored by overexpression of WT RNF168 but not by reintroduction of mutants lacking E3 ligase activity or PAR binding ability. The comet assay also revealed that both PARbinding and ubiquitin-conjugation activities are indispensable for the RNF168-mediated DNA repair process. Taken together, our results suggest that RNF168 acts as a counterpart of PARP1 in DDR and regulates the HR/NHEJ repair processes through the ubiquitination of PARP1.
Keywords: DNA repair, PARP1, PARylation, RNF168, ubiquitination


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