Article

Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 78245-3207, USA.
Nature (Impact Factor: 42.35). 05/2000; 405(6785):473-477. DOI: 10.1038/35013083

ABSTRACT Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive
genetic disorders with susceptibility to cancer and similar cellular phenotypes

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    ABSTRACT: The MRE11/RAD50/NBN (MRN) complex plays a key role in detecting DNA double strand breaks, recruiting and activating ataxia telangiectasia mutated (ATM) and in processing the breaks. Members of this complex also act as adaptor molecules for downstream signaling to the cell cycle and other cellular processes. Somewhat more controversial are the results to support a role for MRN in the ataxia telangiectasia and Rad3-related (ATR) activation and signaling. We provide evidence that RAD50 is required for ATR activation in mammalian cells in response to DNA replication stress. It is in turn phosphorylated at a specific site (S635) by ATR which is required for ATR signaling through Chk1 and other downstream substrates. We find that RAD50 phosphorylation is essential for DNA replication restart by promoting loading of cohesin at these sites. We also demonstrate that replication stress-induced RAD50 phosphorylation is functionally significant for cell survival and cell cycle checkpoint activation. These results highlight the importance of the adaptor role for a member of the MRN complex in all aspects of the response to DNA replication stress.
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