Author:
Bhandari Seema Khattri,Wiest Nathaniel,Sallmyr Annahita,Du Ruofei,Ferry Laure,Defossez Pierre-Antoine,Tomkinson Alan E.
Abstract
AbstractDNA ligase I (LigI), the predominant enzyme that joins Okazaki fragments, interacts with PCNA and Pol δ. LigI also interacts with UHRF1, linking Okazaki fragment joining with DNA maintenance methylation. Okazaki fragments can also be joined by a relatively poorly characterized DNA ligase IIIα (LigIIIα)-dependent backup pathway. Here we examined the effect of LigI-deficiency on proteins at the replication fork. Notably, LigI-deficiency did not alter the kinetics of association of the PCNA clamp, the leading strand polymerase Pol ε, DNA maintenance methylation proteins and core histones with newly synthesized DNA. While the absence of major changes in replication and methylation proteins is consistent with the similar proliferation rate and DNA methylation levels of the LIG1 null cells compared with the parental cells, the increased levels of LigIIIα/XRCC1 and Pol δ at the replication fork and in bulk chromatin indicate that there are subtle replication defects in the absence of LigI. Interestingly, the non-replicative histone H1 variant, H1.0, is enriched in the chromatin of LigI-deficient mouse CH12F3 and human 46BR.1G1 cells. This alteration was not corrected by expression of wild type LigI, suggesting that it is a relatively stable epigenetic change that may contribute to the immunodeficiencies linked with inherited LigI-deficiency syndrome.
Funder
Agence Nationale de la Recherche
LabEx “Who Am I’
Université de Paris IdEx
French Government through its “Investments for the Future” program, Fondation pour la Recherche Médicale and Fondation ARC
NIH
University of New Mexico Cancer center
Publisher
Springer Science and Business Media LLC
Cited by
2 articles.
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