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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Vydáno v:	Molecular cell Ročník 50; číslo 1; s. 116
Hlavní autoři:	Duursma, Anja M, Driscoll, Robert, Elias, Josh E, Cimprich, Karlene A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 11.04.2013
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4164 1097-4164
DOI:	10.1016/j.molcel.2013.03.006