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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| Veröffentlicht in: | Molecular cell Jg. 50; H. 1; S. 116 |
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11.04.2013
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| Abstract | 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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| AbstractList | 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. 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.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. |
| Author | Cimprich, Karlene A Elias, Josh E Driscoll, Robert Duursma, Anja M |
| Author_xml | – sequence: 1 givenname: Anja M surname: Duursma fullname: Duursma, Anja M organization: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA – sequence: 2 givenname: Robert surname: Driscoll fullname: Driscoll, Robert – sequence: 3 givenname: Josh E surname: Elias fullname: Elias, Josh E – sequence: 4 givenname: Karlene A surname: Cimprich fullname: Cimprich, Karlene A |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23582259$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | A role for the MRN complex in ATR activation via TOPBP1 recruitment |
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