title: Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation.
abstract: Telomeres are specialized nucleoprotein complexes that serve as protective caps of linear eukaryotic chromosomes. Loss of telomere function is associated with rampant genetic instability and loss of cellular viability and renewal potential. The telomere also participates in processes of chromosomal repair, as evidenced by the 'capture' or de novo synthesis of telomere repeats at double-stranded breaks and by the capacity of yeast telomeres to serve as repositories of essential components of the DNA repair machinery, particularly those involved in non-homologous end-joining (NHEJ). Here we used the telomerase-deficient mouse, null for the essential telomerase RNA gene (Terc), to assess the role of telomerase and telomere function on the cellular and organismal response to ionizing radiation. Although the loss of telomerase activity per se had no discernable impact on the response to ionizing radiation, the emergence of telomere dysfunction in late-generation Terc-/- mice imparted a radiosensitivity syndrome associated with accelerated mortality. On the cellular level, the gastrointestinal crypt stem cells and primary thymocytes showed increased rates of apoptosis, and mouse embryonic fibroblasts (MEFs) showed diminished dose-dependent clonogenic survival. The radiosensitivity of telomere dysfunctional cells correlated with delayed DNA break repair kinetics, persistent chromosomal breaks and cytogenetic profiles characterized by complex chromosomal aberrations and massive fragmentation. Our findings establish a intimate relationship between functionally intact telomeres and the genomic, cellular and organismal response to ionizing radiation.
authors.affiliation: Department of Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Wong
authors.forename: S
authors.initials: S
authors.lastname: Chang
authors.forename: S R
authors.initials: SR
authors.lastname: Weiler
authors.forename: S
authors.initials: S
authors.lastname: Ganesan
authors.forename: J
authors.initials: J
authors.lastname: Chaudhuri
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.forename: S E
authors.initials: SE
authors.lastname: Artandi
authors.forename: K L
authors.initials: KL
authors.lastname: Rudolph
authors.forename: G J
authors.initials: GJ
authors.lastname: Gottlieb
authors.forename: L
authors.initials: L
authors.lastname: Chin
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
authors.forename: R A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002467:Cell Nucleus / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000528:radiation effects; D053938:DNA Fragmentation / Q000528:radiation effects; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects; D005838:Genotype; D020287:In Situ Nick-End Labeling; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D011836:Radiation Tolerance / Q000235:genetics*; D011839:Radiation, Ionizing; D016615:Telomere / Q000502:physiology* / Q000528:radiation effects / Q000648:ultrastructure; D013950:Thymus Gland / Q000166:cytology / Q000528:radiation effects; D013997:Time Factors