Mre11 Nuclease Activity Has Essential Roles in DNA Repair and Genomic Stability Distinct from ATM Activation

Jeffrey Buis, Yipin Wu, Yibin Deng, Jennifer Leddon, Gerwin Westfield, Mark Eckersdorff, Jo Ann M. Sekiguchi, Sandy Chang, David O. Ferguson

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)85-96
Number of pages12
JournalCell
Volume135
Issue number1
DOIs
StatePublished - Oct 3 2008
Externally publishedYes

Bibliographical note

Funding Information:
Support for this work to D.O.F. was provided by the National Institutes of Health (NIH) (HL079118), Sidney Kimmel Cancer Research Foundation, University of Michigan Cancer Center Support Grant 5-P30-CA46592, and Munn Endowment, and by K08 HL067580 under initial mentorship of Frederick W. Alt. D.O.F. thanks John Moran, Tom Wilson, Mats Ljungman, Chris Canman, and Tobias Else for advice on the manuscript and experiments. S.C. acknowledges M.D. Anderson Cancer Center's Molecular Cytogenetics Core (CA016672) and support from the Welch, Elsa U. Pardee, and Abraham and Phyllis Katz, and Susan G. Komen for the Cure foundations, the Michael Kadoorie Cancer Genetics Research Program, and the NIH (AG028888, CA129037). Y.D. supported by 1K01CA124461-01. J.M.S. is supported by NIH AI063058 and Pew Foundation Scholars Award.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • DNA

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