The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation
The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylat...
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| Veröffentlicht in: | Molecular cancer research 2012-03, Vol.10 (3), p.401-414 |
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| creator | White, David Rafalska-Metcalf, Ilona U Ivanov, Alexey V Corsinotti, Andrea Peng, Hongzhuang Lee, Sheng-Chung Trono, Didier Janicki, Susan M Rauscher, 3rd, Frank J |
| description | The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1α and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, γH2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lack HP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of γH2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin. |
| doi_str_mv | 10.1158/1541-7786.MCR-11-0134 |
| format | Article |
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KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1α and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, γH2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lack HP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of γH2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin.</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-11-0134</identifier><identifier>PMID: 22205726</identifier><language>eng</language><publisher>United States</publisher><subject>Amino Acid Sequence ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Blotting, Western ; Cell Cycle Proteins - metabolism ; Cell Fractionation ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone - metabolism ; DNA Repair ; DNA-Binding Proteins - metabolism ; Gene Knockdown Techniques ; Heterochromatin - metabolism ; Histones - metabolism ; Humans ; Immunohistochemistry ; Mice ; Models, Biological ; Molecular Sequence Data ; Mutant Proteins - chemistry ; Mutant Proteins - metabolism ; NIH 3T3 Cells ; Nuclear Proteins - chemistry ; Nuclear Proteins - metabolism ; Phosphorylation ; Phosphoserine - metabolism ; Protein Serine-Threonine Kinases - metabolism ; Repressor Proteins - chemistry ; Repressor Proteins - metabolism ; Substrate Specificity ; Transgenes - genetics ; Tripartite Motif-Containing Protein 28 ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Molecular cancer research, 2012-03, Vol.10 (3), p.401-414</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-428fef1e538a484e7bb24688629f3d4ebfd5b6198d03604510f0acbf1f34570a3</citedby><cites>FETCH-LOGICAL-c509t-428fef1e538a484e7bb24688629f3d4ebfd5b6198d03604510f0acbf1f34570a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22205726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>White, David</creatorcontrib><creatorcontrib>Rafalska-Metcalf, Ilona U</creatorcontrib><creatorcontrib>Ivanov, Alexey V</creatorcontrib><creatorcontrib>Corsinotti, Andrea</creatorcontrib><creatorcontrib>Peng, Hongzhuang</creatorcontrib><creatorcontrib>Lee, Sheng-Chung</creatorcontrib><creatorcontrib>Trono, Didier</creatorcontrib><creatorcontrib>Janicki, Susan M</creatorcontrib><creatorcontrib>Rauscher, 3rd, Frank J</creatorcontrib><title>The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1α and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, γH2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lack HP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of γH2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Blotting, Western</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Fractionation</subject><subject>Chromobox Protein Homolog 5</subject><subject>Chromosomal Proteins, Non-Histone - metabolism</subject><subject>DNA Repair</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>Heterochromatin - metabolism</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Mutant Proteins - chemistry</subject><subject>Mutant Proteins - metabolism</subject><subject>NIH 3T3 Cells</subject><subject>Nuclear Proteins - chemistry</subject><subject>Nuclear Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Phosphoserine - metabolism</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Repressor Proteins - chemistry</subject><subject>Repressor Proteins - metabolism</subject><subject>Substrate Specificity</subject><subject>Transgenes - genetics</subject><subject>Tripartite Motif-Containing Protein 28</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi1ERT_gJ4B8g0tajz9ihwPSaqG0agsILWfLSSZNUDZO7QRppf54HO1SwYWD5dHM-76a0UPIa2DnAMpcgJKQaW3y87v19wwgYyDkM3ICSulMAFfPl_qgOSanMf5kjDPQ-QtyzDlnSvP8hDxuWqSrzR2Ncxmn4CakN6tvQCs_TMH3kX78sqIBR9cF2g20xQmDr9rgt27qhvdpdD_3qfQDLXf0KjnH4CfshkjdUNOIoRuQSi0uDJd0bH1ML-z2lpfkqHF9xFeH_4z8uPy0WV9lt18_X69Xt1mlWDFlkpsGG0AljJNGoi5LLnNjcl40opZYNrUqcyhMzUTOpALWMFeVDTRCKs2cOCMf9rnjXG6xrjDd5no7hm7rws5619l_J0PX2nv_y0pTSKl5Cnh7CAj-YcY42W0XK-x7N6Cfoy14AZyn3ZLy3X-VwJhJMpkXSar20ir4GAM2TwsBswtju_CzCz-bGKeWXRgn35u_r3ly_YEqfgO1IqL1</recordid><startdate>20120301</startdate><enddate>20120301</enddate><creator>White, David</creator><creator>Rafalska-Metcalf, Ilona U</creator><creator>Ivanov, Alexey V</creator><creator>Corsinotti, Andrea</creator><creator>Peng, Hongzhuang</creator><creator>Lee, Sheng-Chung</creator><creator>Trono, Didier</creator><creator>Janicki, Susan M</creator><creator>Rauscher, 3rd, Frank J</creator><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>7TM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120301</creationdate><title>The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation</title><author>White, David ; Rafalska-Metcalf, Ilona U ; Ivanov, Alexey V ; Corsinotti, Andrea ; Peng, Hongzhuang ; Lee, Sheng-Chung ; Trono, Didier ; Janicki, Susan M ; Rauscher, 3rd, Frank J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-428fef1e538a484e7bb24688629f3d4ebfd5b6198d03604510f0acbf1f34570a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Blotting, Western</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Fractionation</topic><topic>Chromobox Protein Homolog 5</topic><topic>Chromosomal Proteins, Non-Histone - metabolism</topic><topic>DNA Repair</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Gene Knockdown Techniques</topic><topic>Heterochromatin - metabolism</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>Molecular Sequence Data</topic><topic>Mutant Proteins - chemistry</topic><topic>Mutant Proteins - metabolism</topic><topic>NIH 3T3 Cells</topic><topic>Nuclear Proteins - chemistry</topic><topic>Nuclear Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Phosphoserine - metabolism</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Repressor Proteins - chemistry</topic><topic>Repressor Proteins - metabolism</topic><topic>Substrate Specificity</topic><topic>Transgenes - genetics</topic><topic>Tripartite Motif-Containing Protein 28</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>White, David</creatorcontrib><creatorcontrib>Rafalska-Metcalf, Ilona U</creatorcontrib><creatorcontrib>Ivanov, Alexey V</creatorcontrib><creatorcontrib>Corsinotti, Andrea</creatorcontrib><creatorcontrib>Peng, Hongzhuang</creatorcontrib><creatorcontrib>Lee, Sheng-Chung</creatorcontrib><creatorcontrib>Trono, Didier</creatorcontrib><creatorcontrib>Janicki, Susan M</creatorcontrib><creatorcontrib>Rauscher, 3rd, Frank J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>White, David</au><au>Rafalska-Metcalf, Ilona U</au><au>Ivanov, Alexey V</au><au>Corsinotti, Andrea</au><au>Peng, Hongzhuang</au><au>Lee, Sheng-Chung</au><au>Trono, Didier</au><au>Janicki, Susan M</au><au>Rauscher, 3rd, Frank J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2012-03-01</date><risdate>2012</risdate><volume>10</volume><issue>3</issue><spage>401</spage><epage>414</epage><pages>401-414</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1α and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, γH2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lack HP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of γH2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin.</abstract><cop>United States</cop><pmid>22205726</pmid><doi>10.1158/1541-7786.MCR-11-0134</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Animals Ataxia Telangiectasia Mutated Proteins Blotting, Western Cell Cycle Proteins - metabolism Cell Fractionation Chromobox Protein Homolog 5 Chromosomal Proteins, Non-Histone - metabolism DNA Repair DNA-Binding Proteins - metabolism Gene Knockdown Techniques Heterochromatin - metabolism Histones - metabolism Humans Immunohistochemistry Mice Models, Biological Molecular Sequence Data Mutant Proteins - chemistry Mutant Proteins - metabolism NIH 3T3 Cells Nuclear Proteins - chemistry Nuclear Proteins - metabolism Phosphorylation Phosphoserine - metabolism Protein Serine-Threonine Kinases - metabolism Repressor Proteins - chemistry Repressor Proteins - metabolism Substrate Specificity Transgenes - genetics Tripartite Motif-Containing Protein 28 Tumor Suppressor Proteins - metabolism |
| title | The ATM substrate KAP1 controls DNA repair in heterochromatin: regulation by HP1 proteins and serine 473/824 phosphorylation |
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