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

doi:10.1016/j.cell.2006.05.037

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 journal › Article › peer-review

335 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 language	English (US)
Pages (from-to)	49-62
Number of pages	14
Journal	Cell
Volume	126
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2006.05.037
State	Published - Jul 14 2006

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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@article{e29792ad44824da886100dbf38aae9e8,

title = "Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres",

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.",

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

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. ",

year = "2006",

month = jul,

day = "14",

doi = "10.1016/j.cell.2006.05.037",

language = "English (US)",

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journal = "Cell",

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T1 - Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres

AU - Wu, Ling

AU - Multani, Asha S.

AU - He, Hua

AU - Cosme-Blanco, Wilfredo

AU - Deng, Yu

AU - Deng, Jian Min

AU - Bachilo, Olga

AU - Pathak, Sen

AU - Tahara, Hedioshi

AU - Bailey, Susan M.

AU - Deng, Yibin

AU - Behringer, Richard R.

AU - Chang, Sandy

N1 - 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.

PY - 2006/7/14

Y1 - 2006/7/14

N2 - 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.

AB - 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.

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DO - 10.1016/j.cell.2006.05.037

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VL - 126

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EP - 62

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

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