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Author(s) Lansdorp PM Title Repair of telomeric DNA prior to replicative senescence Source MECHANISMS OF AGEING AND DEVELOPMENT 118 (1-2): 23-34 Date 2000 SEP 1 Type Journal : Article LCR: 44   NCR: 76   LCS: 17   GCS: 33 Comment   Address British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Univ British Columbia, Dept Med, Vancouver, BC V6T 2B5, Canada. Reprint Lansdorp, PM, British Columbia Canc Agcy, Terry Fox Lab, 601 West 10th Ave, Vancouver, BC V5Z 1L3, Canada. Abstract The average length of telomere repeats at the ends of chromosomes in most normal human somatic cells has been found to decrease by 50-200 base pairs with each cell division. The loss of telomere repeats has been causally linked to replicative senescence by the demonstration that overexpression of the enzyme telomerase can result in the elongation or maintenance of telomeres 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 importance of telomere shortening and replicative senescence in the homeostasis of cells in renewal tissues and aging. This perspective is concerned with the consequences of telomere shortening at individual chromosomes in individual cells. Experimental evidence indicates that short telomeres accumulate prior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observations are compatible with limited repair of short telomeres by telomerase-dependent or telomerase-independent DNA repair pathways. Deficiencies in telomere repair may result in accelerated senescence and aging as well as genetic instability that facilitates malignant transformation. Examples of molecules that may have a role in the repair of telomeric DNA prior to replicative senescence include ATM, p53, PARP, DNA-PK, Ku70/80, the human hRad50-hMre11-p95 complex, BRCA 1 and 2 and the helicases implicated in Bloom's and Werner's syndrome. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. 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