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Human Molecular Genetics Advance Access published online on August 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi302
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 30, 2005
Revised August 2, 2005
Accepted August 2, 2005

Article

Rad50 depletion impacts upon ATR dependent DNA damage responses

Hui Zhong 1, Alyson Bryson 1, Mark Eckersdorff 1, and David O. Ferguson 1*

1 Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109-0602, USA

* To whom correspondence should be addressed.
David O. Ferguson, E-mail: daviferg{at}umich.edu


  Abstract

The Mre11/Rad50/NBS1 (MRN) complex is mutated in inherited genomic instability syndromes featuring cancer predisposition, mental retardation and immunodeficiency. It functions both in DNA double strand break repair and in controlling the ATM kinase during the response to these lesions. Patients inheriting homozygosity for an NBS1 hypomorphic allele display reduced phosphorylation of signaling factors such as Chk1, but not of the chromatin associated factor H2AX, after stresses that activate the ATM related kinase, ATR. We therefore tested whether MRN has a global controlling role over the ATR kinase through study of MRN deficiencies generated via RNA interference. We show for the first time that MRN is required for ATR dependent phosphorylation of structural maintenance of chromosomes 1 (Smc1), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses. We have uncovered novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR and Smc1, including hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint and a specific pattern of genomic instability. In addition, certain ATR dependent responses do not require MRN. These studies demonstrate that there is indeed a controlling role for MRN over the ATR kinase and have established that the downstream events under this control are broad, including both chromatin associated and diffuse signaling factors, but may not be universal. These studies contribute to our understanding of the central role MRN plays in damage detection and signaling, which serve to maintain genomic stability and resist neoplastic transformation.


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