ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes

Elsa Callén; Mila Jankovic; Simone Difilippantonio; Jeremy A. Daniel; Hua Tang Chen; Arkady Celeste; Manuela Pellegrini; Kevin McBride; Danny Wangsa; Andrea L. Bredemeyer; Barry P. Sleckman; Thomas Ried; Michel Nussenzweig; André Nussenzweig

doi:10.1016/j.cell.2007.06.016

ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes

Elsa Callén, Mila Jankovic, Simone Difilippantonio, Jeremy A. Daniel, Hua Tang Chen, Arkady Celeste, Manuela Pellegrini, Kevin McBride, Danny Wangsa, Andrea L. Bredemeyer, Barry P. Sleckman, Thomas Ried, Michel Nussenzweig, André Nussenzweig

Research output: Contribution to journal › Article › peer-review

158 Scopus citations

Abstract

DNA double-strand breaks (DSBs) induce a signal transmitted by the ataxia-telangiectasia mutated (ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell-cycle checkpoints. Here we show that a significant fraction of mature ATM-deficient lymphocytes contain telomere-deleted ends produced by failed end joining during V(D)J recombination. These RAG-1/2 endonuclease-dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lost ATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long-term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V(D)J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells.

Original language	English (US)
Pages (from-to)	63-75
Number of pages	13
Journal	Cell
Volume	130
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2007.06.016
State	Published - Jul 13 2007
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2007.06.016

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@article{167413dcc5984e0eb675a57f02e1d13e,

title = "ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes",

abstract = "DNA double-strand breaks (DSBs) induce a signal transmitted by the ataxia-telangiectasia mutated (ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell-cycle checkpoints. Here we show that a significant fraction of mature ATM-deficient lymphocytes contain telomere-deleted ends produced by failed end joining during V(D)J recombination. These RAG-1/2 endonuclease-dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lost ATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long-term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V(D)J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells.",

author = "Elsa Call{\'e}n and Mila Jankovic and Simone Difilippantonio and Daniel, {Jeremy A.} and Chen, {Hua Tang} and Arkady Celeste and Manuela Pellegrini and Kevin McBride and Danny Wangsa and Bredemeyer, {Andrea L.} and Sleckman, {Barry P.} and Thomas Ried and Michel Nussenzweig and Andr{\'e} Nussenzweig",

note = "Funding Information: We thank T. Honjo for AID −/− mice; A.Wynshaw-Boris for Atm −/− mice; J. Chen for 53BP1 −/− mice; F. Alt for DNA-PKcs −/− mice; Seth Steinberg for statistical analysis; L. Granger for flow cytometry; L. Stapleton for chromosome-painting probes; K. Murre and M. Kruhlak for help with the 3D FISH; Y. Xu for ATM −/− ES cells; G. Smith for ATM small-molecule inhibitor KU55933; P. Cortes for anti-RAG antibodies; and E. Besmer, O. Fernandez-Capetillo, and A. Bhandoola for comments. A.N. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and a grant from the A-T Children's Project. M.C.N. is supported by grants from NIH. M.C.N. is a Howard Hughes Institute Investigator. The authors declare no financial conflict of interest. ",

year = "2007",

month = jul,

day = "13",

doi = "10.1016/j.cell.2007.06.016",

language = "English (US)",

volume = "130",

pages = "63--75",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes

AU - Callén, Elsa

AU - Jankovic, Mila

AU - Difilippantonio, Simone

AU - Daniel, Jeremy A.

AU - Chen, Hua Tang

AU - Celeste, Arkady

AU - Pellegrini, Manuela

AU - McBride, Kevin

AU - Wangsa, Danny

AU - Bredemeyer, Andrea L.

AU - Sleckman, Barry P.

AU - Ried, Thomas

AU - Nussenzweig, Michel

AU - Nussenzweig, André

N1 - Funding Information: We thank T. Honjo for AID −/− mice; A.Wynshaw-Boris for Atm −/− mice; J. Chen for 53BP1 −/− mice; F. Alt for DNA-PKcs −/− mice; Seth Steinberg for statistical analysis; L. Granger for flow cytometry; L. Stapleton for chromosome-painting probes; K. Murre and M. Kruhlak for help with the 3D FISH; Y. Xu for ATM −/− ES cells; G. Smith for ATM small-molecule inhibitor KU55933; P. Cortes for anti-RAG antibodies; and E. Besmer, O. Fernandez-Capetillo, and A. Bhandoola for comments. A.N. is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and a grant from the A-T Children's Project. M.C.N. is supported by grants from NIH. M.C.N. is a Howard Hughes Institute Investigator. The authors declare no financial conflict of interest.

PY - 2007/7/13

Y1 - 2007/7/13

N2 - DNA double-strand breaks (DSBs) induce a signal transmitted by the ataxia-telangiectasia mutated (ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell-cycle checkpoints. Here we show that a significant fraction of mature ATM-deficient lymphocytes contain telomere-deleted ends produced by failed end joining during V(D)J recombination. These RAG-1/2 endonuclease-dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lost ATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long-term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V(D)J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells.

AB - DNA double-strand breaks (DSBs) induce a signal transmitted by the ataxia-telangiectasia mutated (ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell-cycle checkpoints. Here we show that a significant fraction of mature ATM-deficient lymphocytes contain telomere-deleted ends produced by failed end joining during V(D)J recombination. These RAG-1/2 endonuclease-dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lost ATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long-term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V(D)J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells.

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U2 - 10.1016/j.cell.2007.06.016

DO - 10.1016/j.cell.2007.06.016

M3 - Article

C2 - 17599403

AN - SCOPUS:34447093903

SN - 0092-8674

VL - 130

SP - 63

EP - 75

JO - Cell

JF - Cell

IS - 1

ER -

ATM Prevents the Persistence and Propagation of Chromosome Breaks in Lymphocytes

Abstract

ASJC Scopus subject areas

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