Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescenceReport as inadecuate




Both telomeric and non-telomeric DNA damage are determinants of mammalian cellular senescence - Download this document for free, or read online. Document in PDF available to download.

Epigenetics and Chromatin

, 1:6

First Online: 03 November 2008Received: 25 June 2008Accepted: 03 November 2008

Abstract

BackgroundCellular senescence is a state reached by normal mammalian cells after a finite number of cell divisions and is characterized by morphological and physiological changes including terminal cell-cycle arrest. The limits on cell division imposed by senescence may play an important role in both organismal aging and in preventing tumorigenesis. Cellular senescence and organismal aging are both accompanied by increased DNA damage, seen as the formation of γ-H2AX foci γ-foci, which may be found on uncapped telomeres or at non-telomeric sites of DNA damage. However, the relative importance of telomere- and non-telomere-associated DNA damage to inducing senescence has never been demonstrated. Here we present a new approach to determine accurately the chromosomal location of γ-foci and quantify the number of telomeric versus non-telomeric γ-foci associated with senescence in both human and mouse cells. This approach enables researchers to obtain accurate values and to avoid various possible misestimates inherent in earlier methods.

ResultsUsing combined immunofluorescence and telomere fluorescence in situ hybridization on metaphase chromosomes, we show that human cellular senescence is not solely determined by telomeric DNA damage. In addition, mouse cellular senescence is not solely determined by non-telomeric DNA damage. By comparing cells from different generations of telomerase-null mice with human cells, we show that cells from late generation telomerase-null mice, which have substantially short telomeres, contain mostly telomeric γ-foci. Most notably, we report that, as human and mouse cells approach senescence, all cells exhibit similar numbers of total γ-foci per cell, irrespective of chromosomal locations.

ConclusionOur results suggest that the chromosome location of senescence-related γ-foci is determined by the telomere length rather than species differences per se. In addition, our data indicate that both telomeric and non-telomeric DNA damage responses play equivalent roles in signaling the initiation of cellular senescence and organismal aging. These data have important implications in the study of mechanisms to induce or delay cellular senescence in different species.

List of abbreviationsALTalternative lengthening of telomeres

DSBdouble-strand break

FISHfluorescence in situ hybridization

IMimmortalized MEF

MEFmouse embryonic fibroblast

OXantioxidant tempol

PDpopulation doubling

TERTtelomere reverse transcriptase

WSWerner syndrome

Electronic supplementary materialThe online version of this article doi:10.1186-1756-8935-1-6 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Asako J Nakamura - Y Jeffrey Chiang - Karen S Hathcock - Izumi Horikawa - Olga A Sedelnikova - Richard J Hodes - Willia

Source: https://link.springer.com/







Related documents