PubMed Journals: Genes Dev

  Source:		PMID: 11114888

    		Genes Dev. 2000 Dec 1;14(23):2989-3002.
			Functional interactions between BRCA1 and
			the checkpoint kinase ATR during genotoxic

			Tibbetts RS(1), Cortez D, Brumbaugh KM,
			Scully R, Livingston D, Elledge SJ, Abraham

			Author Information
			(1) Department of Pharmacology and Cancer
			Biology, Duke University Medical Center,
			Durham, North Carolina 27710, USA.

			The BRCA1 gene encodes a tumor suppressor
			that is mutated in 50% of familial breast cancers.
			The BRCA1 protein has been implicated in
			the DNA damage response, as DNA damage induces
			the phosphorylation of BRCA1 and causes
			its recruitment into nuclear foci that contain
			DNA repair proteins. The ataxia-telangiectasia-mutated (ATM) gene
			product controls overall BRCA1 phosphorylation
			in response to gamma-irradiation (IR). In
			this study, we show that BRCA1 phosphorylation
			is only partially ATM dependent in response
			to IR and ATM independent in response to
			treatment with UV light, or the DNA replication
			inhibitors hydroxyurea (HU) and aphidicolin
			(APH). We provide evidence that the kinase
			responsible for this phosphorylation is
			the ATM-related kinase, ATR. ATR phosphorylates
			BRCA1 on six Ser/Thr residues, including
			Ser 1423, in vitro. Increased expression
			of ATR enhanced the phosphorylation of BRCA1
			on Ser 1423 following cellular exposure
			to HU or UV light, whereas doxycycline-induced
			expression of a kinase-inactive ATR mutant
			protein inhibited HU- or UV light-induced
			Ser 1423 phosphorylation in GM847 fibroblasts,
			and partially suppressed the phosphorylation
			of this site in response to IR. Thus, ATR,
			like ATM, controls BRCA1 phosphorylation
			in vivo. Although ATR isolated from DNA-damaged
			cells does not show enhanced kinase activity
			in vitro, we found that ATR responds to
			DNA damage and replication blocks by forming
			distinct nuclear foci at the sites of stalled
			replication forks. Furthermore, ATR nuclear
			foci overlap with the nuclear foci formed
			by BRCA1. The dramatic relocalization of
			ATR in response to DNA damage points to
			a possible mechanism for its ability to
			enhance the phosphorylation of substrates
			in response to DNA damage. Together, these
			results demonstrate that ATR and BRCA1 are
			components of the same genotoxic stress-responsive
			pathway, and that ATR directly phosphorylates
			BRCA1 in response to damaged DNA or stalled
			DNA replication.

			PMCID: PMC317107 PMID: 11114888 [Indexed
			for MEDLINE]

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