Replicative stress, stem cells and aging.

Abstract:

: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), XPD(R722W/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.

journal_name

Mech Ageing Dev

authors

Ruzankina Y,Asare A,Brown EJ

doi

10.1016/j.mad.2008.03.009

subject

Has Abstract

pub_date

2008-07-01 00:00:00

pages

460-6

issue

7-8

eissn

0047-6374

issn

1872-6216

pii

S0047-6374(08)00075-4

journal_volume

129

pub_type

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