DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes

被引：123

作者：

Bredemeyer, Andrea L. ^{[1
]}

Helmink, Beth A. ^{[1
]}

Innes, Cynthia L. ^{[2
,3
]}

Calderon, Boris ^{[1
]}

McGinnis, Lisa M. ^{[1
]}

Mahowald, Grace K. ^{[1
]}

Gapud, Eric J. ^{[1
]}

Walker, Laura M. ^{[1
]}

Collins, Jennifer B. ^{[2
,3
]}

Weaver, Brian K. ^{[1
]}

Mandik-Nayak, Laura ^{[1
]}

Schreiber, Robert D. ^{[1
]}

Allen, Paul M. ^{[1
]}

May, Michael J. ^{[4
]}

Paules, Richard S. ^{[2
,3
]}

Bassing, Craig H. ^{[5
,6
]}

Sleckman, Barry P. ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[2] NIEHS, Environm Stress & Canc Grp, Res Triangle Pk, NC 27709 USA

[3] NIEHS, Microarray Grp, Res Triangle Pk, NC 27709 USA

[4] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Ctr Childhood Canc Res,Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[6] Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

来源：

NATURE | 2008年 / 456卷 / 7223期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nature07392

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 [理学]; 0710 [生物学]; 09 [农学];

摘要：

DNA double- strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell- cycle checkpoints and cell survival(1-5). DNA double- strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double- strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double- strand breaks provide cues that can regulate cell- type- specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.

引用

页码：819 / U113

页数：6

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