Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres

Ling Wu, Asha S. Multani, Hua He, Wilfredo Cosme-Blanco, Yu Deng, Jian Min Deng, Olga Bachilo, Sen Pathak, Hedioshi Tahara, Susan M. Bailey, Yibin Deng, Richard R. Behringer, Sandy Chang

Research output: Contribution to journalArticlepeer-review

292 Scopus citations

Abstract

The terminal t-loop structure adopted by mammalian telomeres is thought to prevent telomeres from being recognized as double-stranded DNA breaks by sequestering the 3′ single-stranded G-rich overhang from exposure to the DNA damage machinery. The POT1 (protection of telomeres) protein binds the single-stranded overhang and is required for both chromosomal end protection and telomere length regulation. The mouse genome contains two POT1 orthologs, Pot1a and Pot1b. Here we show that conditional deletion of Pot1a elicits a DNA damage response at telomeres, resulting in p53-dependent replicative senescence. Pot1a-deficient cells exhibit overall telomere length and 3′ overhang elongation as well as aberrant homologous recombination (HR) at telomeres, manifested as increased telomere sister chromatid exchanges and formation of telomere circles. Telomeric HR following Pot1a loss requires NBS1. Pot1a deletion also results in chromosomal instability. Our results suggest that POT1a is crucial for the maintenance of both telomere integrity and overall genomic stability.

Original languageEnglish (US)
Pages (from-to)49-62
Number of pages14
JournalCell
Volume126
Issue number1
DOIs
StatePublished - Jul 14 2006
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to Peter Baumann for Pot1a BAC clones, Jan Karlseder for providing Trf1 antibody, Philip Carpenter for the 53BP1 antibody, Ronald DePinho for the pKOII vector, and Edwin H. Goodwin for statistical analyses. We acknowledge the MDACC Cytogenetics Core and the GEM facility for outstanding services (NCI #CA016672). We thank Peter Baumann, Guillermina Lozano, and members of the Chang lab for helpful comments. S.M.B. was supported by NASA #NNJ04HK83G. S.C. acknowledges generous financial support from the Welch Foundation, the Elsa U. Pardee Foundation, the Sidney Kimmel Foundation for Cancer Research, the Abraham and Phyllis Katz Foundation, and the Michael Kadoorie Cancer Genetic Research Program.

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