Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM-Deficient Lymphocytes
The DNA double-strand break (DSB) repair protein DNA-PKcs and the signal transducer ATM are both activated by DNA breaks and phosphorylate similar substrates in vitro, yet appear to have distinct functions in vivo. Here, we show that ATM and DNA-PKcs have overlapping functions in lymphocytes. Ablati...
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| Veröffentlicht in: | Molecular cell 2009-05, Vol.34 (3), p.285-297 |
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| creator | Callén, Elsa Jankovic, Mila Wong, Nancy Zha, Shan Chen, Hua-Tang Difilippantonio, Simone Di Virgilio, Michela Heidkamp, Gordon Alt, Frederick W. Nussenzweig, André Nussenzweig, Michel |
| description | The DNA double-strand break (DSB) repair protein DNA-PKcs and the signal transducer ATM are both activated by DNA breaks and phosphorylate similar substrates in vitro, yet appear to have distinct functions in vivo. Here, we show that ATM and DNA-PKcs have overlapping functions in lymphocytes. Ablation of both kinase activities in cells undergoing immunoglobulin class switch recombination leads to a compound defect in switching and a synergistic increase in chromosomal fragmentation, DNA insertions, and translocations due to aberrant processing of DSBs. These abnormalities are attributed to a compound deficiency in phosphorylation of key proteins required for DNA repair, class switching, and cell death. Notably, both kinases are required for normal levels of p53 phosphorylation in B and T cells and p53-dependent apoptosis. Our experiments reveal a DNA-PKcs-dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM. |
| doi_str_mv | 10.1016/j.molcel.2009.04.025 |
| format | Article |
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Here, we show that ATM and DNA-PKcs have overlapping functions in lymphocytes. Ablation of both kinase activities in cells undergoing immunoglobulin class switch recombination leads to a compound defect in switching and a synergistic increase in chromosomal fragmentation, DNA insertions, and translocations due to aberrant processing of DSBs. These abnormalities are attributed to a compound deficiency in phosphorylation of key proteins required for DNA repair, class switching, and cell death. Notably, both kinases are required for normal levels of p53 phosphorylation in B and T cells and p53-dependent apoptosis. 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Our experiments reveal a DNA-PKcs-dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM.</description><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Base Sequence</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cells, Cultured</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA Repair</subject><subject>DNA-Activated Protein Kinase - genetics</subject><subject>DNA-Activated Protein Kinase - metabolism</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - physiology</subject><subject>Genomic Instability</subject><subject>Immunoglobulin Class Switching</subject><subject>Lymphocytes - cytology</subject><subject>Lymphocytes - physiology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular Sequence Data</subject><subject>MOLIMMUNO</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>PROTEINS</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Thymus Gland - cytology</subject><subject>Tripartite Motif-Containing Protein 28</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAQtSqqfsE_QMgnbgm2147XF6Sl2wLq8qFSzpZjT1gvSZza2Ur773HYVVsunDzyvPdm5j2EXlNSUkKrd5uyC62FtmSEqJLwkjBxhM4oUbLgtOIvDjWTlThF5yltCKFczNUJOqWKCyKYPEPrq5SgH71p8W1oATch4uXXRfH9xibs-6nGy7CtWyh-jNH0Dn-IYH7jWxiMj3j6WAxhGEPyf_GLuy_FEhpvfVbFq103rIPdjZBeouPGtAleHd4L9PP66u7yU7H69vHz5WJVWF7RsZgbxmYSnCBWMMeIk1aomiuhCJ_LfBahYGpruHMA3NqZEHUtZ5ll66YWfHaB3u91h23dgbN5jWhaPUTfmbjTwXj9b6f3a_0rPGgms1uKZYG3B4EY7reQRt35lH1uTQ9hm3QlmajmRGUg3wNtDClFaB6HUKKniPRG7yPSU0SacJ0jyrQ3zxd8Ih0yeboAsk0PHqJOk5sWnI9gR-2C__-EP10KpRc</recordid><startdate>20090515</startdate><enddate>20090515</enddate><creator>Callén, Elsa</creator><creator>Jankovic, Mila</creator><creator>Wong, Nancy</creator><creator>Zha, Shan</creator><creator>Chen, Hua-Tang</creator><creator>Difilippantonio, Simone</creator><creator>Di Virgilio, Michela</creator><creator>Heidkamp, Gordon</creator><creator>Alt, Frederick W.</creator><creator>Nussenzweig, André</creator><creator>Nussenzweig, Michel</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090515</creationdate><title>Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM-Deficient Lymphocytes</title><author>Callén, Elsa ; Jankovic, Mila ; Wong, Nancy ; Zha, Shan ; Chen, Hua-Tang ; Difilippantonio, Simone ; Di Virgilio, Michela ; Heidkamp, Gordon ; Alt, Frederick W. ; Nussenzweig, André ; Nussenzweig, Michel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-8a2237ed50c52d20d7c59b4959048716401eabca4ddee4cc355bb73a22cbfb543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Base Sequence</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cells, Cultured</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA Repair</topic><topic>DNA-Activated Protein Kinase - genetics</topic><topic>DNA-Activated Protein Kinase - metabolism</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - physiology</topic><topic>Genomic Instability</topic><topic>Immunoglobulin Class Switching</topic><topic>Lymphocytes - cytology</topic><topic>Lymphocytes - physiology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Sequence Data</topic><topic>MOLIMMUNO</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>PROTEINS</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Thymus Gland - cytology</topic><topic>Tripartite Motif-Containing Protein 28</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Callén, Elsa</creatorcontrib><creatorcontrib>Jankovic, Mila</creatorcontrib><creatorcontrib>Wong, Nancy</creatorcontrib><creatorcontrib>Zha, Shan</creatorcontrib><creatorcontrib>Chen, Hua-Tang</creatorcontrib><creatorcontrib>Difilippantonio, Simone</creatorcontrib><creatorcontrib>Di Virgilio, Michela</creatorcontrib><creatorcontrib>Heidkamp, Gordon</creatorcontrib><creatorcontrib>Alt, Frederick W.</creatorcontrib><creatorcontrib>Nussenzweig, André</creatorcontrib><creatorcontrib>Nussenzweig, Michel</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Callén, Elsa</au><au>Jankovic, Mila</au><au>Wong, Nancy</au><au>Zha, Shan</au><au>Chen, Hua-Tang</au><au>Difilippantonio, Simone</au><au>Di Virgilio, Michela</au><au>Heidkamp, Gordon</au><au>Alt, Frederick W.</au><au>Nussenzweig, André</au><au>Nussenzweig, Michel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM-Deficient Lymphocytes</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2009-05-15</date><risdate>2009</risdate><volume>34</volume><issue>3</issue><spage>285</spage><epage>297</epage><pages>285-297</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>The DNA double-strand break (DSB) repair protein DNA-PKcs and the signal transducer ATM are both activated by DNA breaks and phosphorylate similar substrates in vitro, yet appear to have distinct functions in vivo. Here, we show that ATM and DNA-PKcs have overlapping functions in lymphocytes. Ablation of both kinase activities in cells undergoing immunoglobulin class switch recombination leads to a compound defect in switching and a synergistic increase in chromosomal fragmentation, DNA insertions, and translocations due to aberrant processing of DSBs. These abnormalities are attributed to a compound deficiency in phosphorylation of key proteins required for DNA repair, class switching, and cell death. Notably, both kinases are required for normal levels of p53 phosphorylation in B and T cells and p53-dependent apoptosis. Our experiments reveal a DNA-PKcs-dependent pathway that regulates DNA repair and activation of p53 in the absence of ATM.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19450527</pmid><doi>10.1016/j.molcel.2009.04.025</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis - physiology Ataxia Telangiectasia Mutated Proteins Base Sequence Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cells, Cultured DNA DNA Breaks, Double-Stranded DNA Repair DNA-Activated Protein Kinase - genetics DNA-Activated Protein Kinase - metabolism DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Fibroblasts - cytology Fibroblasts - physiology Genomic Instability Immunoglobulin Class Switching Lymphocytes - cytology Lymphocytes - physiology Mice Mice, Knockout Molecular Sequence Data MOLIMMUNO Nuclear Proteins - genetics Nuclear Proteins - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism PROTEINS Repressor Proteins - genetics Repressor Proteins - metabolism Thymus Gland - cytology Tripartite Motif-Containing Protein 28 Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism |
| title | Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM-Deficient Lymphocytes |
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