Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break Repair

R. Scott Williams; Gabriel Moncalian; Jessica S. Williams; Yoshiki Yamada; Oliver Limbo; David S. Shin; Lynda M. Groocock; Dana Cahill; Chiharu Hitomi; Grant Guenther; Davide Moiani; James P. Carney; Paul Russell; John A. Tainer

doi:10.1016/j.cell.2008.08.017

Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break Repair

R. Scott Williams, Gabriel Moncalian, Jessica S. Williams, Yoshiki Yamada, Oliver Limbo, David S. Shin, Lynda M. Groocock, Dana Cahill, Chiharu Hitomi, Grant Guenther, Davide Moiani, James P. Carney, Paul Russell, John A. Tainer

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

380 Scopus citations

Abstract

Mre11 forms the core of the multifunctional Mre11-Rad50-Nbs1 (MRN) complex that detects DNA double-strand breaks (DSBs), activates the ATM checkpoint kinase, and initiates homologous recombination (HR) repair of DSBs. To define the roles of Mre11 in both DNA bridging and nucleolytic processing during initiation of DSB repair, we combined small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11 dimers bound to DNA with mutational analyses of fission yeast Mre11. The Mre11 dimer adopts a four-lobed U-shaped structure that is critical for proper MRN complex assembly and for binding and aligning DNA ends. Further, mutations blocking Mre11 endonuclease activity impair cell survival after DSB induction without compromising MRN complex assembly or Mre11-dependant recruitment of Ctp1, an HR factor, to DSBs. These results show how Mre11 dimerization and nuclease activities initiate repair of DSBs and collapsed replication forks, as well as provide a molecular foundation for understanding cancer-causing Mre11 mutations in ataxia telangiectasia-like disorder (ATLD).

Original language	English (US)
Pages (from-to)	97-109
Number of pages	13
Journal	Cell
Volume	135
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2008.08.017
State	Published - Oct 3 2008
Externally published	Yes

Keywords

DNA

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2008.08.017

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@article{6d3a9d6e19384e6abf405f427ef24362,

title = "Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break Repair",

abstract = "Mre11 forms the core of the multifunctional Mre11-Rad50-Nbs1 (MRN) complex that detects DNA double-strand breaks (DSBs), activates the ATM checkpoint kinase, and initiates homologous recombination (HR) repair of DSBs. To define the roles of Mre11 in both DNA bridging and nucleolytic processing during initiation of DSB repair, we combined small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11 dimers bound to DNA with mutational analyses of fission yeast Mre11. The Mre11 dimer adopts a four-lobed U-shaped structure that is critical for proper MRN complex assembly and for binding and aligning DNA ends. Further, mutations blocking Mre11 endonuclease activity impair cell survival after DSB induction without compromising MRN complex assembly or Mre11-dependant recruitment of Ctp1, an HR factor, to DSBs. These results show how Mre11 dimerization and nuclease activities initiate repair of DSBs and collapsed replication forks, as well as provide a molecular foundation for understanding cancer-causing Mre11 mutations in ataxia telangiectasia-like disorder (ATLD).",

keywords = "DNA",

author = "Williams, {R. Scott} and Gabriel Moncalian and Williams, {Jessica S.} and Yoshiki Yamada and Oliver Limbo and Shin, {David S.} and Groocock, {Lynda M.} and Dana Cahill and Chiharu Hitomi and Grant Guenther and Davide Moiani and Carney, {James P.} and Paul Russell and Tainer, {John A.}",

note = "Funding Information: R.S.W. is supported by the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research, and the Skaggs Institute for Chemical Biology fellowships. Y.Y. is supported by a Uehara Memorial Foundation fellowship. Work on the Mre11 complex in the authors' laboratories is supported in part by National Cancer Institute grants CA117638, CA92584, and CA77325. Lawrence Berkeley National Laboratory efforts are supported in part by U.S. Department of Energy programs IDAT (for Integrating crystallography and X-ray scattering) and MAGGIE (for defining Pyrococus complexes) under contract number DE-AC02-05CH11231. We thank Scott Classen, Michal Hammel, Greg Hura, and Susan Tsutakawa for assistance with SAXS and X-ray data collection at the Advanced Light Source SIBYLS beamline and Brian Chapados for discussions and comments. ",

year = "2008",

month = oct,

day = "3",

doi = "10.1016/j.cell.2008.08.017",

language = "English (US)",

volume = "135",

pages = "97--109",

journal = "Cell",

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publisher = "Cell Press",

number = "1",

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T1 - Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break Repair

AU - Williams, R. Scott

AU - Moncalian, Gabriel

AU - Williams, Jessica S.

AU - Yamada, Yoshiki

AU - Limbo, Oliver

AU - Shin, David S.

AU - Groocock, Lynda M.

AU - Cahill, Dana

AU - Hitomi, Chiharu

AU - Guenther, Grant

AU - Moiani, Davide

AU - Carney, James P.

AU - Russell, Paul

AU - Tainer, John A.

N1 - Funding Information: R.S.W. is supported by the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research, and the Skaggs Institute for Chemical Biology fellowships. Y.Y. is supported by a Uehara Memorial Foundation fellowship. Work on the Mre11 complex in the authors' laboratories is supported in part by National Cancer Institute grants CA117638, CA92584, and CA77325. Lawrence Berkeley National Laboratory efforts are supported in part by U.S. Department of Energy programs IDAT (for Integrating crystallography and X-ray scattering) and MAGGIE (for defining Pyrococus complexes) under contract number DE-AC02-05CH11231. We thank Scott Classen, Michal Hammel, Greg Hura, and Susan Tsutakawa for assistance with SAXS and X-ray data collection at the Advanced Light Source SIBYLS beamline and Brian Chapados for discussions and comments.

PY - 2008/10/3

Y1 - 2008/10/3

N2 - Mre11 forms the core of the multifunctional Mre11-Rad50-Nbs1 (MRN) complex that detects DNA double-strand breaks (DSBs), activates the ATM checkpoint kinase, and initiates homologous recombination (HR) repair of DSBs. To define the roles of Mre11 in both DNA bridging and nucleolytic processing during initiation of DSB repair, we combined small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11 dimers bound to DNA with mutational analyses of fission yeast Mre11. The Mre11 dimer adopts a four-lobed U-shaped structure that is critical for proper MRN complex assembly and for binding and aligning DNA ends. Further, mutations blocking Mre11 endonuclease activity impair cell survival after DSB induction without compromising MRN complex assembly or Mre11-dependant recruitment of Ctp1, an HR factor, to DSBs. These results show how Mre11 dimerization and nuclease activities initiate repair of DSBs and collapsed replication forks, as well as provide a molecular foundation for understanding cancer-causing Mre11 mutations in ataxia telangiectasia-like disorder (ATLD).

AB - Mre11 forms the core of the multifunctional Mre11-Rad50-Nbs1 (MRN) complex that detects DNA double-strand breaks (DSBs), activates the ATM checkpoint kinase, and initiates homologous recombination (HR) repair of DSBs. To define the roles of Mre11 in both DNA bridging and nucleolytic processing during initiation of DSB repair, we combined small-angle X-ray scattering (SAXS) and crystal structures of Pyrococcus furiosus Mre11 dimers bound to DNA with mutational analyses of fission yeast Mre11. The Mre11 dimer adopts a four-lobed U-shaped structure that is critical for proper MRN complex assembly and for binding and aligning DNA ends. Further, mutations blocking Mre11 endonuclease activity impair cell survival after DSB induction without compromising MRN complex assembly or Mre11-dependant recruitment of Ctp1, an HR factor, to DSBs. These results show how Mre11 dimerization and nuclease activities initiate repair of DSBs and collapsed replication forks, as well as provide a molecular foundation for understanding cancer-causing Mre11 mutations in ataxia telangiectasia-like disorder (ATLD).

KW - DNA

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DO - 10.1016/j.cell.2008.08.017

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AN - SCOPUS:52949149420

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JO - Cell

JF - Cell

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Mre11 Dimers Coordinate DNA End Bridging and Nuclease Processing in Double-Strand-Break Repair

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Keywords

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