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Nucleic Acids Res January 1, 2021; 49 (9): 5003-5016.

HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation.

Kumamoto S , Nishiyama A , Chiba Y , Miyashita R , Konishi C , Azuma Y , Nakanishi M .

DNA ligase 1 (LIG1) is known as the major DNA ligase responsible for Okazaki fragment joining. Recent studies have implicated LIG3 complexed with XRCC1 as an alternative player in Okazaki fragment joining in cases where LIG1 is not functional, although the underlying mechanisms are largely unknown. Here, using a cell-free system derived from Xenopus egg extracts, we demonstrated the essential role of PARP1-HPF1 in LIG3-dependent Okazaki fragment joining. We found that Okazaki fragments were eventually ligated even in the absence of LIG1, employing in its place LIG3-XRCC1, which was recruited onto chromatin. Concomitantly, LIG1 deficiency induces ADP-ribosylation of histone H3 in a PARP1-HPF1-dependent manner. The depletion of PARP1 or HPF1 resulted in a failure to recruit LIG3 onto chromatin and a subsequent failure in Okazaki fragment joining in LIG1-depleted extracts. Importantly, Okazaki fragments were not ligated at all when LIG1 and XRCC1 were co-depleted. Our results suggest that a unique form of ADP-ribosylation signaling promotes the recruitment of LIG3 on chromatin and its mediation of Okazaki fragment joining as a backup system for LIG1 perturbation.

PubMed ID: 33872376
PMC ID: PMC8136790
Article link: Nucleic Acids Res
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: atad5 dna2 exo1 fen1 hpf1 lig1 lig3 parg parp1 pcna xrcc1
GO keywords: DNA repair [+]

Disease Ontology terms: cancer

Article Images: [+] show captions
References [+] :
Abdou, DNA ligase III acts as a DNA strand break sensor in the cellular orchestration of DNA strand break repair. 2015, Pubmed, Xenbase