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Mol Cell. 2015 Feb 5;57(3):479-91. doi: 10.1016/j.molcel.2014.12.018. Epub 2015 Jan 15.

Interdependence of the rad50 hook and globular domain functions.

Author information

1
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
2
Laboratory of Chemical Biology, University of Wrocław, Joliot-Curie 14a, 50-383 Wrocław, Poland.
3
Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avenida Américo Vespucio, 41092 Sevilla, Spain.
4
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. Electronic address: petrinij@mskcc.org.

Abstract

Rad50 contains a conserved Zn(2+) coordination domain (the Rad50 hook) that functions as a homodimerization interface. Hook ablation phenocopies Rad50 deficiency in all respects. Here, we focused on rad50 mutations flanking the Zn(2+)-coordinating hook cysteines. These mutants impaired hook-mediated dimerization, but recombination between sister chromatids was largely unaffected. This may reflect that cohesin-mediated sister chromatid interactions are sufficient for double-strand break repair. However, Mre11 complex functions specified by the globular domain, including Tel1 (ATM) activation, nonhomologous end joining, and DNA double-strand break end resection were affected, suggesting that dimerization exerts a broad influence on Mre11 complex function. These phenotypes were suppressed by mutations within the coiled-coil and globular ATPase domains, suggesting a model in which conformational changes in the hook and globular domains are transmitted via the extended coils of Rad50. We propose that transmission of spatial information in this manner underlies the regulation of Mre11 complex functions.

PMID:
25601756
PMCID:
PMC4527088
DOI:
10.1016/j.molcel.2014.12.018
[Indexed for MEDLINE]
Free PMC Article

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