A role for the MRN complex in ATR activation via TOPBP1 recruitment

The MRN (MRE11-RAD50-NBS1) complex has been implicated in many aspects of the DNA damage response. It has key roles in sensing and processing DNA double-strand breaks, as well as in activation of ATM (ataxia telangiectasia mutated). We reveal a function for MRN in ATR (ATM- and RAD3-related) activat...

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Bibliographic Details
Published in:Molecular cell Vol. 50; no. 1; p. 116
Main Authors: Duursma, Anja M, Driscoll, Robert, Elias, Josh E, Cimprich, Karlene A
Format: Journal Article
Language:English
Published: United States 11.04.2013
Subjects:
Animals
Ataxia Telangiectasia Mutated Proteins
Binding Sites
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Checkpoint Kinase 1
Chromosomal Proteins, Non-Histone - metabolism
DNA, Single-Stranded - chemistry
DNA, Single-Stranded - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzyme Activation
Humans
MRE11 Homologue Protein
Multiprotein Complexes
Nucleic Acid Conformation
Phosphorylation
Protein Binding
Protein Kinases - metabolism
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
RNA Interference
Transfection
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Xenopus laevis - genetics
Xenopus laevis - metabolism
Xenopus Proteins - genetics
Xenopus Proteins - metabolism
ISSN:1097-4164, 1097-4164
Online Access:Get more information
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Summary:The MRN (MRE11-RAD50-NBS1) complex has been implicated in many aspects of the DNA damage response. It has key roles in sensing and processing DNA double-strand breaks, as well as in activation of ATM (ataxia telangiectasia mutated). We reveal a function for MRN in ATR (ATM- and RAD3-related) activation by using defined ATR-activating DNA structures in Xenopus egg extracts. Strikingly, we demonstrate that MRN is required for recruitment of TOPBP1 to an ATR-activating structure that contains a single-stranded DNA (ssDNA) and a double-stranded DNA (dsDNA) junction and that this recruitment is necessary for phosphorylation of CHK1. We also show that the 911 (RAD9-RAD1-HUS1) complex is not required for TOPBP1 recruitment but is essential for TOPBP1 function. Thus, whereas MRN is required for TOPBP1 recruitment at an ssDNA-to-dsDNA junction, 911 is required for TOPBP1 "activation." These findings provide molecular insights into how ATR is activated.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2013.03.006