Oxidation products of 5-methylcytosine are decreased in senescent cells andtissues of progeroid mice

Ewelina Zarakowska, Jolanta Czerwinska, Agnieszka Tupalska, Matt J. Yousefzadeh, Siobhán Q. Gregg, Claudette M.St Croix, Laura J. Niedernhofer, Marek Foksinski, Daniel Gackowski, Anna Szpila, Marta Starczak, Barbara Tudek, Ryszard Olinski

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

5-Hydroxymethylcytosine and 5-formylcytosine are stable DNA base modifications generated from 5-methylcytosine by the ten-eleven translocation protein family that function as epigenetic markers. 5-Hydroxymethyluracil may also be generated from thymine by ten-eleven translocation enzymes. Here, we asked if these epigenetic changes accumulate in senescent cells, since they are thought to be inversely correlated with proliferation. Testing this in ERCC1-XPF-deficient cells and mice also enabled discovery if these DNA base changes are repaired by nucleotide excision repair. Epigenetic marks were measured in proliferating, quiescent and senescent wild-type (WT) and Ercc1−/− primary mouse embryonic fibroblasts. The pattern of epigenetic marks depended more on the proliferation status of the cells than their DNA repair capacity. The cytosine modifications were all decreased in senescent cells compared to quiescent or proliferating cells, whereas 5-(hydroxymethyl)-2′-deoxyuridine was increased. In vivo, both 5-(hydroxymethyl)-2′-deoxyuridine and 5-(hydroxymethyl)-2′-deoxycytidine were significantly increased in liver tissues of aged WT mice compared to young adult WT mice. Livers of Ercc1-deficient mice with premature senescence and aging had reduced level of 5-(hydroxymethyl)-2′-deoxycytidine and 5-formyl-2′-deoxycytidine compared to aged-matched WT controls. Taken together, we demonstrate for the first time, that 5-(hydroxymethyl)-2′-deoxycytidine is significantly reduced in senescent cells and tissue, potentially yielding a novel marker of senescence.

Original languageEnglish (US)
Pages (from-to)1003-1009
Number of pages7
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume73
Issue number8
DOIs
StatePublished - Jul 9 2018

Bibliographical note

Funding Information:
This work was supported by the National Science Centre (grant number DEC-2012/07/B/NZ1/00008 (R.O.), http://www.ncn.gov.pl, and Ministry of Science and Higher Education, grant number N N303 819540 (B.T.). L.J.N., M.J.Y., and C.M.S. were supported by NIH/NIA P01 AG043376. J.C. was supported by the Human Capital Operational Programme 1/POKL/4.3/2012 “Modern Methods, Medicines and Treatments from the Viewpoint of Healthcare and Economy in the 21st-Century Europe - Interdisciplinary Education in Biomedical Sciences, 2nd and 3rd Cycle Studies”.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Keywords

  • 5-formylcytosine
  • 5-hydroxymethylcytosine
  • 5-hydroxymethyluracil
  • Aging
  • ERCC1-XPF endonuclease

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