Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation

被引：262

作者：

Buis, Jeffrey ^{[1
]}

Wu, Yipin ^{[1
]}

Deng, Yibin ^{[2
,3
]}

Leddon, Jennifer ^{[1
]}

Westfield, Gerwin ^{[4
,5
]}

Eckersdorff, Mark ^{[1
]}

Sekiguchi, JoAnn M. ^{[4
,5
]}

Chang, Sandy ^{[2
,3
]}

Ferguson, David O. ^{[1
]}

机构：

[1] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[2] Univ Texas Houston, MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[3] Univ Texas Houston, MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

[4] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

来源：

CELL | 2008年 / 135卷 / 01期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1016/j.cell.2008.08.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The Mre11/Rad50/NBS1 (MRN) complex maintains genomic stability by bridging DNA ends and initiating DNA damage signaling through activation of the ATM kinase. Mre11 possesses DNA nuclease activities that are highly conserved in evolution but play unknown roles in mammals. To define the functions of Mre11, we engineered targeted mouse alleles that either abrogate nuclease activities or inactivate the entire MRN complex. Mre11 nuclease deficiency causes a striking array of phenotypes indistinguishable from the absence of MRN, including early embryonic lethality and dramatic genomic instability. We identify a crucial role for the nuclease activities in homology-directed double-strand-break repair and a contributing role in activating the ATR kinase. However, the nuclease activities are not required to activate ATM after DNA damage or telomere deprotection. Therefore, nucleolytic processing by Mre11 is an essential function of fundamental importance in DNA repair, distinct from MRN control of ATM signaling.

引用

页码：85 / 96

页数：12

共 46 条

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