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PMID: 15123826 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

DNA end joining becomes less efficient and more error-prone during cellular senescence.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 20 ·2004-05-18 ·Pages 7624-9

Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V

Abstract

Accumulation of somatic mutations is thought to contribute to the aging process. Genomic instability has been shown to increase during aging, suggesting an aberrant function of DNA double-strand break (DSB) repair. Surprisingly, DSB repair has not been examined with respect to cellular senescence. Therefore, we have studied the ability of young, presenescent, and senescent normal human fibroblasts to repair DSBs in transfected DNA by using a fluorescent reporter substrate. We have found that the efficiency of end joining is reduced up to 4.5 fold in presenescent and senescent cells, relative to young cells. Sequence analysis of end junctions showed that the frequency of precise ligation was higher in young cells, whereas end joining in old cells was associated with extended deletions. These results indicate that end joining becomes inefficient and more error-prone during cellular senescence. Furthermore, the ability to use microhomologies for end joining was compromised in senescent cells, suggesting that young and senescent cells may use different end joining pathways. We hypothesize that inefficient and aberrant end joining is a likely mechanism underlying the age-related genomic instability and higher incidence of cancer in the elderly.

MeSH Terms
Cellular Senescence/physiology DNA/metabolism DNA Repair/physiology Flow Cytometry Genes, Reporter Genomic Instability/physiology Humans Mutation/physiology Sequence Deletion/physiology
Chemicals
DNA
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Seluanov Andrei
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Mittelman David
Pereira-Smith Olivia M
Wilson John H
Gorbunova Vera
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0400726101
Published
2004-05-18
Epub
2004-00-28
Pages
7624-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC419656
Subset
IM
Grants
NEI NIH HHS · R01 EY011731 · United States
NIGMS NIH HHS · R01 GM038219 · United States
NEI NIH HHS · EY11731 · United States
NIGMS NIH HHS · GM38219 · United States
External Links
PubMed source DOI: 10.1073/pnas.0400726101 PMC Full Text View journal details
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