XPF-ERCC1 protects liver, kidney and blood homeostasis outside the canonical excision repair pathways
Mulderrig, Lee; Garaycoechea, Juan I
(2020) PLoS Genetics, volume 16, issue 4, pp. 1 - 21
(Article)
Abstract
Loss of the XPF-ERCC1 endonuclease causes a dramatic phenotype that results in progeroid features associated with liver, kidney and bone marrow dysfunction. As this nuclease is involved in multiple DNA repair transactions, it is plausible that this severe phenotype results from the simultaneous inactivation of both branches of nucleotide excision
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repair (GG- and TC-NER) and Fanconi anaemia (FA) inter-strand crosslink (ICL) repair. Here we use genetics in human cells and mice to investigate the interaction between the canonical NER and ICL repair pathways and, subsequently, how their joint inactivation phenotypically overlaps with XPF-ERCC1 deficiency. We find that cells lacking TC-NER are sensitive to crosslinking agents and that there is a genetic interaction between NER and FA in the repair of certain endogenous crosslinking agents. However, joint inactivation of GG-NER, TC-NER and FA crosslink repair cannot account for the hypersensitivity of XPF-deficient cells to classical crosslinking agents nor is it sufficient to explain the extreme phenotype of Ercc1-/- mice. These analyses indicate that XPF-ERCC1 has important functions outside of its central role in NER and FA crosslink repair which are required to prevent endogenous DNA damage. Failure to resolve such damage leads to loss of tissue homeostasis in mice and humans.
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Keywords: Animals, Blood, Cross-Linking Reagents/pharmacology, DNA Damage, DNA Repair/genetics, DNA-Binding Proteins/deficiency, Endonucleases/deficiency, Female, Formaldehyde/pharmacology, Homeostasis, Humans, Kidney/enzymology, Liver/enzymology, Male, Mice, Genetics(clinical), Genetics, Ecology, Evolution, Behavior and Systematics, Molecular Biology, Cancer Research, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 1553-7390
Publisher: Public Library of Science
Note: Funding Information: This work was supported by the MRC Laboratory of Molecular Biology. L.M. is supported by a CRUK Program grant awarded to Ketan J. Patel. J.I.G. was supported by the Wellcome Trust Investigator Grant awarded to Ketan J. Patel, King?s College, Cambridge and the Hubrecht Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Publisher Copyright: © 2020 Mulderrig, Garaycoechea. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
(Peer reviewed)