HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation
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Issue Date
2021-04-19Author
Kumamoto, Soichiro
Nishiyama, Atsuya
Chiba, Yoshie
Miyashita, Ryota
Konishi, Chieko
Azuma, Yoshiaki
Nakanishi, Makoto
Publisher
Oxford University Press
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
Copyright: The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
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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.
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Citation
Soichiro Kumamoto, Atsuya Nishiyama, Yoshie Chiba, Ryota Miyashita, Chieko Konishi, Yoshiaki Azuma, Makoto Nakanishi, HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation, Nucleic Acids Research, Volume 49, Issue 9, 21 May 2021, Pages 5003–5016, https://doi.org/10.1093/nar/gkab269
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