Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 129, Issue 7-8, Pages 460-466Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2008.03.009
Keywords
ATR; replication fork stability; stem cells; aging; telomeres
Categories
Funding
- NIA NIH HHS [1R01 AG 027376, R01 AG027376-02, R01 AG027376] Funding Source: Medline
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DNA synthesis is a remarkably vulnerable phase in the cell cycle. In addition to introduction of errors during semi-conservative replication, the inherently labile structure of the replication fork, as well as numerous pitfalls encountered in the course of fork progression, make the normally stable double stranded molecule susceptible to collapse and recombination. As described in this issue, maintenance of genome integrity in the face of such events is essential to prevent the premature onset of age-related diseases. At the organismal level, the roles for such maintenance are numerous; however, the preservation of stem and progenitor cell pools may be particularly important as indicated by several genetically engineered mouse models. Stresses on stem and progenitor cell pools, in the form of telomere shortening (Terc(-/-)) or other genome maintenance failures (ATR(mko), Ku86(-/-), LIG4(Y288C), XPDR722W/R722W, etc.), have been shown to degrade tissue renewal capacity and accelerate the appearance of age-related phenotypes. In the case of telomere shortening, exhaustion of replicative potential appears to be at least partially dependent on the cell cycle regulatory component of the DNA damage response. Therefore, both the genome maintenance mechanisms that counter DNA damage and the cell cycle checkpoint responses to damage strongly influence the onset of age-related diseases and do so, at least in part, by affecting long-term stem and progenitor cell potential. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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