NDLI: Telomere shortening alters the kinetics of the DNA damage response after ionizing radiation in human cells

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Drissi, Rachid Wu, Jing Hu, Yafang Bockhold, Carol Dome, Jeffrey S.
Description	Country affiliation: United States Author Affiliation: Drissi R ( Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. rachid.drissi@cchmc.org)
Abstract	Studies of telomerase-deficient mice and human cell lines have demonstrated that telomere shortening enhances sensitivity to ionizing radiation (IR). The molecular basis for this observation remains unclear. To better understand the connection between telomere shortening and radiation sensitivity, we evaluated components of the DNA damage response pathway in normal human fibroblasts with short and long telomeres. Late-passage cells with short telomeres showed enhanced sensitivity to IR compared to early-passage cells with longer telomeres. Compared to early-passage cells, late-passage cells had a higher baseline level of phosphorylated H2AX protein (γH2AX) before IR, but diminished peak levels of H2AX phosphorylation after IR. Both the appearance and disappearance of γH2AX foci were delayed in late-passage cells, indicative of delayed DNA repair. In contrast to the situation with H2AX, ATM and p53 phosphorylation kinetics were similar in early and late-passage cells, but phosphorylation of the chromatin-bound ATM targets SMC1 and NBS1 was delayed in late-passage cells. Because impaired phosphorylation associated with short telomeres was restricted to chromatin-bound ATM targets, chromatin structure was assessed. DNA from cells with short telomeres was more resistant to digestion with micrococcal nuclease, indicative of compacted chromatin. Moreover, cells with short telomeres showed histone acetylation and methylation profiles consistent with heterochromatin. Together our data suggest a model in which short telomeres induce chromatin structure changes that limit access of activated ATM to its downstream targets on the chromatin, thereby providing a potential explanation for the increased radiation sensitivity seen with telomere shortening.
File Format	HTM / HTML
ISSN	19406207
e-ISSN	19406215
DOI	10.1158/1940-6207.CAPR-11-0069
Journal	Cancer Prevention Research
Issue Number	12
Volume Number	4
Language	English
Publisher	American Association for Cancer Research
Publisher Date	2011-12-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Oncology Chromatin Genetics Dna Damage Radiation Effects Radiation, Ionizing Telomere Shortening Telomere Acetylation Ataxia Telangiectasia Mutated Proteins Blotting, Western Cell Cycle Proteins Metabolism Dna Methylation Dna Repair Dna-binding Proteins Fluorescent Antibody Technique Hela Cells Histones Immunoprecipitation Kinetics Phosphorylation Protein-serine-threonine Kinases Radiation Tolerance Telomerase Tumor Suppressor Proteins Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology

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