Repair of telomeric DNA prior to replicative senescence

Authors
Citation
Pm. Lansdorp, Repair of telomeric DNA prior to replicative senescence, MECH AGE D, 118(1-2), 2000, pp. 23-34
Citations number
76
Categorie Soggetti
Cell & Developmental Biology
Journal title
MECHANISMS OF AGEING AND DEVELOPMENT
ISSN journal
00476374 → ACNP
Volume
118
Issue
1-2
Year of publication
2000
Pages
23 - 34
Database
ISI
SICI code
0047-6374(20000901)118:1-2<23:ROTDPT>2.0.ZU;2-4
Abstract
The average length of telomere repeats at the ends of chromosomes in most n ormal human somatic cells has been found to decrease by 50-200 base pairs w ith each cell division. The loss of telomere repeats has been causally link ed to replicative senescence by the demonstration that overexpression of th e enzyme telomerase can result in the elongation or maintenance of telomere s and immortalization of somatic cells with a diploid and apparently normal karyotype. Major questions that remain are related to the actual mechanism by which telomere shortening induces replicative senescence and the import ance of telomere shortening and replicative senescence in the homeostasis o f cells in renewal tissues and aging. This perspective is concerned with th e consequences of telomere shortening at individual chromosomes in individu al cells. Experimental evidence indicates that short telomeres accumulate p rior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observat ions are compatible with limited repair of short telomeres by telomerase-de pendent or telomerase-independent DNA repair pathways. Deficiencies in telo mere repair may result in accelerated senescence and aging as well as genet ic instability that facilitates malignant transformation. Examples of molec ules that may have a role in the repair of telomeric DNA prior to replicati ve senescence include ATM, p53, PARP, DNA-PK, Ku70/80, the human hRad50-hMr e11-p95 complex, BRCA 1 and 2 and the helicases implicated in Bloom's and W erner's syndrome. (C) 2000 Elsevier Science Ireland Ltd. All rights reserve d.