Open AccessDelayed kinetics of DNA double‐strand break processing in normal and pathological aging
Author(s) -
Sedelnikova Olga A.,
Horikawa Izumi,
Redon Christophe,
Nakamura Asako,
Zimonjic Drazen B.,
Popescu Nicholas C.,
Bonner William M.
Publication year - 2008
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2007.00354.x
Subject(s) - genome instability , biology , dna damage , telomere , senescence , histone , werner syndrome , endogeny , chromosome instability , premature aging , dna repair , dna , carcinogenesis , microbiology and biotechnology , genetics , cancer , gene , chromosome , biochemistry , rna , helicase
Summary Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age‐dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage‐induced foci of phosphorylated histone H2AX (γ‐H2AX), which occurs specifically at sites of DNA double‐strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous γ‐H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of γ‐H2AX foci than those taken from normal donors of comparable age. Further increases in γ‐H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to γ‐H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of γ‐H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of γ‐H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging.