The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair
CtIP plays an important role in homologous recombination (HR)-mediated DNA double-stranded break (DSB) repair and interacts with Nbs1 and BRCA1, which are linked to Nijmegen breakage syndrome (NBS) and familial breast cancer, respectively. We identified new CDK phosphorylation sites on CtIP and foun...
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| creator | Wang, Hailong Shi, Linda Z Wong, Catherine C L Han, Xuemei Hwang, Patty Yi-Hwa Truong, Lan N Zhu, Qingyuan Shao, Zhengping Chen, David J Berns, Michael W Yates, 3rd, John R Chen, Longchuan Wu, Xiaohua |
| description | CtIP plays an important role in homologous recombination (HR)-mediated DNA double-stranded break (DSB) repair and interacts with Nbs1 and BRCA1, which are linked to Nijmegen breakage syndrome (NBS) and familial breast cancer, respectively. We identified new CDK phosphorylation sites on CtIP and found that phosphorylation of these newly identified CDK sites induces association of CtIP with the N-terminus FHA and BRCT domains of Nbs1. We further showed that these CDK-dependent phosphorylation events are a prerequisite for ATM to phosphorylate CtIP upon DNA damage, which is important for end resection to activate HR by promoting recruitment of BLM and Exo1 to DSBs. Most notably, this CDK-dependent CtIP and Nbs1 interaction facilitates ATM to phosphorylate CtIP in a substrate-specific manner. These studies reveal one important mechanism to regulate cell-cycle-dependent activation of HR upon DNA damage by coupling CDK- and ATM-mediated phosphorylation of CtIP through modulating the interaction of CtIP with Nbs1, which significantly helps to understand how DSB repair is regulated in mammalian cells to maintain genome stability. |
| doi_str_mv | 10.1371/journal.pgen.1003277 |
| format | Article |
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We identified new CDK phosphorylation sites on CtIP and found that phosphorylation of these newly identified CDK sites induces association of CtIP with the N-terminus FHA and BRCT domains of Nbs1. We further showed that these CDK-dependent phosphorylation events are a prerequisite for ATM to phosphorylate CtIP upon DNA damage, which is important for end resection to activate HR by promoting recruitment of BLM and Exo1 to DSBs. Most notably, this CDK-dependent CtIP and Nbs1 interaction facilitates ATM to phosphorylate CtIP in a substrate-specific manner. These studies reveal one important mechanism to regulate cell-cycle-dependent activation of HR upon DNA damage by coupling CDK- and ATM-mediated phosphorylation of CtIP through modulating the interaction of CtIP with Nbs1, which significantly helps to understand how DSB repair is regulated in mammalian cells to maintain genome stability.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1003277</identifier><identifier>PMID: 23468639</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Ataxia Telangiectasia Mutated Proteins ; Biology ; BRCA1 Protein - genetics ; BRCA1 Protein - metabolism ; Breast cancer ; Cancer ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Cycle - genetics ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cyclin-Dependent Kinases - genetics ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded ; DNA damage ; DNA repair ; DNA Repair - genetics ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Endodeoxyribonucleases ; Genetic aspects ; Genetics ; Genomic Instability ; HEK293 Cells ; HeLa Cells ; Homologous Recombination ; Humans ; Kinases ; Mutation ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Phosphorylation ; Physiological aspects ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Yeast</subject><ispartof>PLoS genetics, 2013-02, Vol.9 (2), p.e1003277-e1003277</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Wang H, Shi LZ, Wong CCL, Han X, Hwang PY-H, et al. (2013) The Interaction of CtIP and Nbs1 Connects CDK and ATM to Regulate HR-Mediated Double-Strand Break Repair. PLoS Genet 9(2): e1003277. doi:10.1371/journal.pgen.1003277</rights><rights>2013 Wang et al 2013 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c792t-266a2a65cb57719ede44ab2ad758ddcdbec774051ace880830032901a72fd1dd3</citedby><cites>FETCH-LOGICAL-c792t-266a2a65cb57719ede44ab2ad758ddcdbec774051ace880830032901a72fd1dd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585124/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585124/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23468639$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Hailong</creatorcontrib><creatorcontrib>Shi, Linda Z</creatorcontrib><creatorcontrib>Wong, Catherine C L</creatorcontrib><creatorcontrib>Han, Xuemei</creatorcontrib><creatorcontrib>Hwang, Patty Yi-Hwa</creatorcontrib><creatorcontrib>Truong, Lan N</creatorcontrib><creatorcontrib>Zhu, Qingyuan</creatorcontrib><creatorcontrib>Shao, Zhengping</creatorcontrib><creatorcontrib>Chen, David J</creatorcontrib><creatorcontrib>Berns, Michael W</creatorcontrib><creatorcontrib>Yates, 3rd, John R</creatorcontrib><creatorcontrib>Chen, Longchuan</creatorcontrib><creatorcontrib>Wu, Xiaohua</creatorcontrib><title>The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>CtIP plays an important role in homologous recombination (HR)-mediated DNA double-stranded break (DSB) repair and interacts with Nbs1 and BRCA1, which are linked to Nijmegen breakage syndrome (NBS) and familial breast cancer, respectively. We identified new CDK phosphorylation sites on CtIP and found that phosphorylation of these newly identified CDK sites induces association of CtIP with the N-terminus FHA and BRCT domains of Nbs1. We further showed that these CDK-dependent phosphorylation events are a prerequisite for ATM to phosphorylate CtIP upon DNA damage, which is important for end resection to activate HR by promoting recruitment of BLM and Exo1 to DSBs. Most notably, this CDK-dependent CtIP and Nbs1 interaction facilitates ATM to phosphorylate CtIP in a substrate-specific manner. These studies reveal one important mechanism to regulate cell-cycle-dependent activation of HR upon DNA damage by coupling CDK- and ATM-mediated phosphorylation of CtIP through modulating the interaction of CtIP with Nbs1, which significantly helps to understand how DSB repair is regulated in mammalian cells to maintain genome stability.</description><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Biology</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA1 Protein - metabolism</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Cycle - genetics</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cyclin-Dependent Kinases - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>DNA Repair - genetics</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Endodeoxyribonucleases</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Genomic Instability</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Homologous Recombination</subject><subject>Humans</subject><subject>Kinases</subject><subject>Mutation</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Yeast</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVk01v1DAQhiMEoqXwDxBEQkJwyBLHTuxckFbLR1eUFpWFq-XYk6zbbLzYDoJ_j7ObVhvUAygHW-NnXvudyUTRU5TOEKbozZXpbSfa2baBbobSFGeU3ouOUZ7jhJKU3D_YH0WPnLsKTM5K-jA6yjApWIHL42i9WkOsOw9WSK9NF5s6Xvjll1h0Kj6vHIql6TqQ3sWLd5920fnqc-xNbKHpW-EhPr1MNqB02KpYmb5qIXHeDmRlQVwHcCu0fRw9qEXr4Mm4nkTfPrxfLU6Ts4uPy8X8LJG0zHySFYXIRJHLKqcUlaCAEFFlQtGcKSVVBZIGRzkSEhhLGR6MlykSNKsVUgqfRM_3utvWOD4WyXGEEQmmi5wEYrknlBFXfGv1Rtjf3AjNdwFjGy6s17IFzoq0qIkoWJVRgktcljkigIhSKCvVTuvteFtfhSJI6ILzdiI6Pen0mjfmJw-dyFE2CLwaBaz50YPzfKOdhLYVHZh-9-68wHnAA_riL_RudyPViGBAd7UJ98pBlM9DpVjJGEOBmt1BhU_BRoeOQ61DfJLwepIQGA-_fCN65_jy6-V_sOf_zl58n7IvD9g1iNavnWn74b91U5DsQWmNcxbq24aglA_Dc1M5PgwPH4cnpD07bOZt0s204D_yFxEf</recordid><startdate>20130201</startdate><enddate>20130201</enddate><creator>Wang, Hailong</creator><creator>Shi, Linda Z</creator><creator>Wong, Catherine C L</creator><creator>Han, Xuemei</creator><creator>Hwang, Patty Yi-Hwa</creator><creator>Truong, Lan N</creator><creator>Zhu, Qingyuan</creator><creator>Shao, Zhengping</creator><creator>Chen, David J</creator><creator>Berns, Michael W</creator><creator>Yates, 3rd, John R</creator><creator>Chen, Longchuan</creator><creator>Wu, Xiaohua</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130201</creationdate><title>The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair</title><author>Wang, Hailong ; Shi, Linda Z ; Wong, Catherine C L ; Han, Xuemei ; Hwang, Patty Yi-Hwa ; Truong, Lan N ; Zhu, Qingyuan ; Shao, Zhengping ; Chen, David J ; Berns, Michael W ; Yates, 3rd, John R ; Chen, Longchuan ; Wu, Xiaohua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c792t-266a2a65cb57719ede44ab2ad758ddcdbec774051ace880830032901a72fd1dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Biology</topic><topic>BRCA1 Protein - genetics</topic><topic>BRCA1 Protein - metabolism</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell Cycle - genetics</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cyclin-Dependent Kinases - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>DNA Repair - genetics</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Endodeoxyribonucleases</topic><topic>Genetic aspects</topic><topic>Genetics</topic><topic>Genomic Instability</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Homologous Recombination</topic><topic>Humans</topic><topic>Kinases</topic><topic>Mutation</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Hailong</creatorcontrib><creatorcontrib>Shi, Linda Z</creatorcontrib><creatorcontrib>Wong, Catherine C L</creatorcontrib><creatorcontrib>Han, Xuemei</creatorcontrib><creatorcontrib>Hwang, Patty Yi-Hwa</creatorcontrib><creatorcontrib>Truong, Lan N</creatorcontrib><creatorcontrib>Zhu, Qingyuan</creatorcontrib><creatorcontrib>Shao, Zhengping</creatorcontrib><creatorcontrib>Chen, David J</creatorcontrib><creatorcontrib>Berns, Michael W</creatorcontrib><creatorcontrib>Yates, 3rd, John R</creatorcontrib><creatorcontrib>Chen, Longchuan</creatorcontrib><creatorcontrib>Wu, Xiaohua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Hailong</au><au>Shi, Linda Z</au><au>Wong, Catherine C L</au><au>Han, Xuemei</au><au>Hwang, Patty Yi-Hwa</au><au>Truong, Lan N</au><au>Zhu, Qingyuan</au><au>Shao, Zhengping</au><au>Chen, David J</au><au>Berns, Michael W</au><au>Yates, 3rd, John R</au><au>Chen, Longchuan</au><au>Wu, Xiaohua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2013-02-01</date><risdate>2013</risdate><volume>9</volume><issue>2</issue><spage>e1003277</spage><epage>e1003277</epage><pages>e1003277-e1003277</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>CtIP plays an important role in homologous recombination (HR)-mediated DNA double-stranded break (DSB) repair and interacts with Nbs1 and BRCA1, which are linked to Nijmegen breakage syndrome (NBS) and familial breast cancer, respectively. We identified new CDK phosphorylation sites on CtIP and found that phosphorylation of these newly identified CDK sites induces association of CtIP with the N-terminus FHA and BRCT domains of Nbs1. We further showed that these CDK-dependent phosphorylation events are a prerequisite for ATM to phosphorylate CtIP upon DNA damage, which is important for end resection to activate HR by promoting recruitment of BLM and Exo1 to DSBs. Most notably, this CDK-dependent CtIP and Nbs1 interaction facilitates ATM to phosphorylate CtIP in a substrate-specific manner. These studies reveal one important mechanism to regulate cell-cycle-dependent activation of HR upon DNA damage by coupling CDK- and ATM-mediated phosphorylation of CtIP through modulating the interaction of CtIP with Nbs1, which significantly helps to understand how DSB repair is regulated in mammalian cells to maintain genome stability.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23468639</pmid><doi>10.1371/journal.pgen.1003277</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Ataxia Telangiectasia Mutated Proteins Biology BRCA1 Protein - genetics BRCA1 Protein - metabolism Breast cancer Cancer Carrier Proteins - genetics Carrier Proteins - metabolism Cell Cycle - genetics Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cyclin-Dependent Kinases - genetics Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded DNA damage DNA repair DNA Repair - genetics DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Endodeoxyribonucleases Genetic aspects Genetics Genomic Instability HEK293 Cells HeLa Cells Homologous Recombination Humans Kinases Mutation Nuclear Proteins - genetics Nuclear Proteins - metabolism Phosphorylation Physiological aspects Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Yeast |
| title | The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair |
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