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p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice.

Published version
Peer-reviewed

Repository DOI


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Authors

Bona, Nazareno 
Smink, Job 
Crisp, Alastair 

Abstract

DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.

Description

Acknowledgements: We thank the Human Research Tissue Bank for processing histological samples. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. We would like to thank C. Knox, C. Watson, L. Tredgett, J. Clark, the Ares and Biomed staff for assistance with animal procedures and experimentation. We thank M. Daly, F. Zhang, P. Penttila and the Flow Cytometry Core staff for their technical assistance. We would like to thank C. Perez for assisting with the generation of RNA sequencing libraries. Funding was provided by the Medical Research Council as part of UK Research and Innovation file reference no. MC_UP_1201/18 (G.P.C., R.J.H, N.B., H.W. and A.C.) and Hubrecht Institute (J.I.G.), Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) project number OCENW.M20.113 (J.S.).

Keywords

Animals, Humans, Mice, DNA Damage, DNA Repair, DNA-Binding Proteins, Tumor Suppressor Protein p53, Xeroderma Pigmentosum

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

15

Publisher

Springer Science and Business Media LLC
Sponsorship
RCUK | Medical Research Council (MRC) (MC_UP_1201/18)
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research) (OCENW.M20.113)