biostudies-literatureYan ZDepartment of Education of Hebei Province ()| Natural Science Foundation of Hebei Province ()National Natural Science Foundation of China (NSFC)e70959https://www.ebi.ac.uk/biostudies/studies/S-EPMC12363383biostudies-literatureUnknown39(16)Poly (ADP-ribosyl)ation (PARylation) plays a crucial role in DNA replication, particularly during S phase, where it is detected at replication sites on the lagging strand to facilitate Okazaki fragment processing. However, the role of dePARylation in DNA replication remains elusive. In this study, we demonstrate that poly (ADP-ribose) glycohydrolase (PARG) is actively involved in degrading poly (ADP-ribose) at DNA replication sites during S phase. Inhibition of PARG in S-phase cells leads to the accumulation of DNA single-strand breaks at replication sites. Furthermore, suppression of dePARylation during S phase impairs DNA replication, which can be rescued by wild-type PARG but not by a catalytically inactive PARG mutant. Mechanistically, we show that PCNA, a key factor in DNA replicationFASEB journal : official publication of the Federation of American Societies for Experimental BiologyPoly (ADP-Ribose) Glycohydrolase-Dependent dePARylation of PCNA Is Essential for DNA Replication.PMC1236338382002594H202420102432071277HJYB202522Yang XLiu XLi HYan ZJiang XWu CHan XGuo SWang YQiao ZCheng XFeng QfalsePoly (ADP-Ribose) Glycohydrolase-Dependent dePARylation of PCNA Is Essential for DNA Replication.Poly (ADP-ribosyl)ation (PARylation) plays a crucial role in DNA replication, particularly during S phase, where it is detected at replication sites on the lagging strand to facilitate Okazaki fragment processing. However, the role of dePARylation in DNA replication remains elusive. In this study, we demonstrate that poly (ADP-ribose) glycohydrolase (PARG) is actively involved in degrading poly (ADP-ribose) at DNA replication sites during S phase. Inhibition of PARG in S-phase cells leads to the accumulation of DNA single-strand breaks at replication sites. Furthermore, suppression of dePARylation during S phase impairs DNA replication, which can be rescued by wild-type PARG but not by a catalytically inactive PARG mutant. Mechanistically, we show that PCNA, a key factor in DNA replication2025-01-01T00:00:00Z2025 Aug2026-05-01T01:44:02.174Z2026-04-07T16:33:10.445ZS-EPMC123633834082786610.1096/fj.202403378R