, a bio/informatics shared resource is still "open for business" - Visit the CDS website

Function of a conserved checkpoint recruitment domain in ATRIP proteins.

Ball HL, Ehrhardt MR, Mordes DA, Glick GG, Chazin WJ, Cortez D
Mol Cell Biol. 2007 27 (9): 3367-77

PMID: 17339343 · PMCID: PMC1899971 · DOI:10.1128/MCB.02238-06

The ATR (ATM and Rad3-related) kinase is essential to maintain genomic integrity. ATR is recruited to DNA lesions in part through its association with ATR-interacting protein (ATRIP), which in turn interacts with the single-stranded DNA binding protein RPA (replication protein A). In this study, a conserved checkpoint protein recruitment domain (CRD) in ATRIP orthologs was identified by biochemical mapping of the RPA binding site in combination with nuclear magnetic resonance, mutagenesis, and computational modeling. Mutations in the CRD of the Saccharomyces cerevisiae ATRIP ortholog Ddc2 disrupt the Ddc2-RPA interaction, prevent proper localization of Ddc2 to DNA breaks, sensitize yeast to DNA-damaging agents, and partially compromise checkpoint signaling. These data demonstrate that the CRD is critical for localization and optimal DNA damage responses. However, the stimulation of ATR kinase activity by binding of topoisomerase binding protein 1 (TopBP1) to ATRIP-ATR can occur independently of the interaction of ATRIP with RPA. Our results support the idea of a multistep model for ATR activation that requires separable localization and activation functions of ATRIP.

MeSH Terms (23)

Adaptor Proteins, Signal Transducing Amino Acid Sequence Animals Binding Sites Cell Cycle Cell Cycle Proteins DNA, Fungal DNA-Binding Proteins DNA Damage Exodeoxyribonucleases Humans Magnetic Resonance Imaging Models, Molecular Molecular Sequence Data Phosphoproteins Protein Binding Protein Structure, Tertiary Replication Protein A Saccharomyces cerevisiae Saccharomyces cerevisiae Proteins Sequence Alignment Structural Homology, Protein Transcription Factors

Connections (2)

This publication is referenced by other Labnodes entities: