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      Five dysfunctional telomeres predict onset of senescence in human cells

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          Abstract

          Replicative senescence is accompanied by a telomere-specific DNA damage response (DDR). We found that DDR+ telomeres occur spontaneously in early-passage normal human cells and increase in number with increasing cumulative cell divisions. DDR+ telomeres at replicative senescence retain TRF2 and RAP1 proteins, are not associated with end-to-end fusions and mostly result from strand-independent, postreplicative dysfunction. On the basis of the calculated number of DDR+ telomeres in G1-phase cells just before senescence and after bypassing senescence by inactivation of wild-type p53 function, we conclude that the accrual of five telomeres in G1 that are DDR+ but nonfusogenic is associated with p53-dependent senescence.

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          DNA damage foci at dysfunctional telomeres.

          Hiroyuki Takai, Agata Smogorzewska, Titia de Lange (2003)
          We report cytologic and genetic data indicating that telomere dysfunction induces a DNA damage response in mammalian cells. Dysfunctional, uncapped telomeres, created through inhibition of TRF2, became associated with DNA damage response factors, such as 53BP1, gamma-H2AX, Rad17, ATM, and Mre11. We refer to the domain of telomere-associated DNA damage factors as a Telomere Dysfunction-Induced Focus (TIF). The accumulation of 53BP1 on uncapped telomeres was reduced in the presence of the PI3 kinase inhibitors caffeine and wortmannin, which affect ATM, ATR, and DNA-PK. By contrast, Mre11 TIFs were resistant to caffeine, consistent with previous findings on the Mre11 response to ionizing radiation. A-T cells had a diminished 53BP1 TIF response, indicating that the ATM kinase is a major transducer of this pathway. However, in the absence of ATM, TRF2 inhibition still induced TIFs and senescence, pointing to a second ATM-independent pathway. We conclude that the cellular response to telomere dysfunction is governed by proteins that also control the DNA damage response. TIFs represent a new tool for evaluating telomere status in normal and malignant cells suspected of harboring dysfunctional telomeres. Furthermore, induction of TIFs through TRF2 inhibition provides an opportunity to study the DNA damage response within the context of well-defined, physically marked lesions.
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            Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.

            Laure Crabbé, Ramiro Verdun, Candy Haggblom … (2004)
            Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.
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              Senescence induced by altered telomere state, not telomere loss.

              Jan Karlseder, Agata Smogorzewska, Titia de Lange (2002)
              Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO Rep
                Title: EMBO Reports
                Publisher: Nature Publishing Group
                ISSN (Print): 1469-221X
                ISSN (Electronic): 1469-3178
                Publication date (Print): January 2012
                Publication date (Electronic): 09 December 2011
                Publication date PMC-release: 09 December 2011
                Volume: 13
                Issue: 1
                Pages: 52-59
                Affiliations
                [1 ]Cancer Research Unit, Children's Medical Research Institute , 214 Hawkesbury Road, Westmead, New South Wales 2145, Australia
                [2 ]Sydney Medical School, University of Sydney , Sydney, New South Wales 2006, Australia
                Author notes
                [a ]Tel: + 612 8865 2901; Fax: + 612 8865 2860; E-mail: rreddel@ 123456cmri.org.au
                [†]

                Present address: Molecular and Cellular Biology Department, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037-1099, USA

                Article
                Publisher Item ID: embor2011227
                DOI: 10.1038/embor.2011.227
                PMC ID: 3246253
                PubMed ID: 22157895
                SO-VID: eac7732c-ac6a-426c-ae43-a1f410bae57f
                Copyright © Copyright © 2012, European Molecular Biology Organization
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial No Derivative Works 3.0 Unported License, which permits distribution and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

                History
                Date received : 13 June 2011
                Date revision received : 11 October 2011
                Date accepted : 25 October 2011
                Categories
                Subject: Scientific Reports

                ScienceOpen disciplines: Molecular biology
                Keywords: telomeres,dna damage response,senescence
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: telomeres, dna damage response, senescence

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