A Targeted DNA-PKcs-Null Mutation Reveals DNA-PK-Independent Functions for KU in V(D)J Recombination
The DNA-dependent protein kinase (DNA-PK) consists of Ku70, Ku80, and a large catalytic subunit, DNA-PKcs. Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 1998-09, Vol.9 (3), p.367-376 |
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| container_title | Immunity (Cambridge, Mass.) |
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| creator | Gao, Yijie Chaudhuri, Jayanta Zhu, Chengming Davidson, Laurie Weaver, David T Alt, Frederick W |
| description | The DNA-dependent protein kinase (DNA-PK) consists of Ku70, Ku80, and a large catalytic subunit, DNA-PKcs. Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with severe growth retardation plus immunodeficiency in mice. In contrast, we now demonstrate that DNA-PKcs-null mice generated by gene-targeted mutation, while also severely immunodeficient, exhibit no growth retardation. Furthermore, DNA-PKcs-null cells are blocked for V(D)J coding-end joining, but retain normal RS-end joining. Finally, while DNA-PK-null fibroblasts exhibited increased IR sensitivity, DNA-PKcs-deficient ES cells did not. We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs. |
| doi_str_mv | 10.1016/S1074-7613(00)80619-6 |
| format | Article |
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Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with severe growth retardation plus immunodeficiency in mice. In contrast, we now demonstrate that DNA-PKcs-null mice generated by gene-targeted mutation, while also severely immunodeficient, exhibit no growth retardation. Furthermore, DNA-PKcs-null cells are blocked for V(D)J coding-end joining, but retain normal RS-end joining. Finally, while DNA-PK-null fibroblasts exhibited increased IR sensitivity, DNA-PKcs-deficient ES cells did not. 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We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs.</description><subject>Animals</subject><subject>Antigens, Nuclear</subject><subject>DNA Helicases</subject><subject>DNA-Activated Protein Kinase</subject><subject>DNA-Binding Proteins - physiology</subject><subject>Embryo, Mammalian</subject><subject>Female</subject><subject>Fibroblasts - enzymology</subject><subject>Fibroblasts - radiation effects</subject><subject>Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics</subject><subject>Gene Targeting</subject><subject>Immunoglobulin Joining Region - genetics</subject><subject>Ku Autoantigen</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mutation - genetics</subject><subject>Nuclear Proteins - physiology</subject><subject>Phenotype</subject><subject>Protein-Serine-Threonine Kinases - biosynthesis</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - physiology</subject><subject>Radiation, Ionizing</subject><subject>Severe Combined Immunodeficiency - genetics</subject><subject>Signal Transduction</subject><subject>Stem Cells - enzymology</subject><subject>Stem Cells - metabolism</subject><subject>Stem Cells - physiology</subject><subject>Stem Cells - radiation effects</subject><subject>Thymus Gland - cytology</subject><subject>Thymus Gland - physiology</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1v1DAQtRColMJPqOQTag8u48Qf8QmtWgqlpSBouVqOPUFG2WRrJ5X493h3o157mRnpfYz0HiHHHM44cPXhFwctmFa8PgE4bUBxw9QLcsjBaCZ4Ay-390J5Td7k_BeAC2nggBwYrRot1SEJK3rn0h-cMNCL2xX7ce0zu537nn6bJzfFcaA_8RFdnxeYXQ0BN1jGMNHLefBbTqbdmOj1PY0D_X1ycfq1iPy4buOws3hLXnXFAd8t-4jcX366O__Cbr5_vjpf3TAvpZqYMGi0ByWMaTWAbzwIiRBqJ6FDpzVHYSoRqi5Ulauglqg96rbpXDCtrOoj8n7vu0njw4x5suuYPfa9G3Ccs1XGSGFKHM8RuZIlK14XotwTfRpzTtjZTYprl_5ZDnZbg93VYLcZWwC7q8GqojteHsztGsOTasm94B_3OJY4HiMmm33EwWOICf1kwxif-fAfjAOU4g</recordid><startdate>19980901</startdate><enddate>19980901</enddate><creator>Gao, Yijie</creator><creator>Chaudhuri, Jayanta</creator><creator>Zhu, Chengming</creator><creator>Davidson, Laurie</creator><creator>Weaver, David T</creator><creator>Alt, Frederick W</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>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19980901</creationdate><title>A Targeted DNA-PKcs-Null Mutation Reveals DNA-PK-Independent Functions for KU in V(D)J Recombination</title><author>Gao, Yijie ; Chaudhuri, Jayanta ; Zhu, Chengming ; Davidson, Laurie ; Weaver, David T ; Alt, Frederick W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c556t-49e97c06499b700c8c045e0d3a50fea771e4924d2fd22a2035e7ce7b8fad9b523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Antigens, Nuclear</topic><topic>DNA Helicases</topic><topic>DNA-Activated Protein Kinase</topic><topic>DNA-Binding Proteins - physiology</topic><topic>Embryo, Mammalian</topic><topic>Female</topic><topic>Fibroblasts - enzymology</topic><topic>Fibroblasts - radiation effects</topic><topic>Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics</topic><topic>Gene Targeting</topic><topic>Immunoglobulin Joining Region - genetics</topic><topic>Ku Autoantigen</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mutation - genetics</topic><topic>Nuclear Proteins - physiology</topic><topic>Phenotype</topic><topic>Protein-Serine-Threonine Kinases - biosynthesis</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - physiology</topic><topic>Radiation, Ionizing</topic><topic>Severe Combined Immunodeficiency - genetics</topic><topic>Signal Transduction</topic><topic>Stem Cells - enzymology</topic><topic>Stem Cells - metabolism</topic><topic>Stem Cells - physiology</topic><topic>Stem Cells - radiation effects</topic><topic>Thymus Gland - cytology</topic><topic>Thymus Gland - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gao, Yijie</creatorcontrib><creatorcontrib>Chaudhuri, Jayanta</creatorcontrib><creatorcontrib>Zhu, Chengming</creatorcontrib><creatorcontrib>Davidson, Laurie</creatorcontrib><creatorcontrib>Weaver, David T</creatorcontrib><creatorcontrib>Alt, Frederick W</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>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Immunity (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gao, Yijie</au><au>Chaudhuri, Jayanta</au><au>Zhu, Chengming</au><au>Davidson, Laurie</au><au>Weaver, David T</au><au>Alt, Frederick W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Targeted DNA-PKcs-Null Mutation Reveals DNA-PK-Independent Functions for KU in V(D)J Recombination</atitle><jtitle>Immunity (Cambridge, Mass.)</jtitle><addtitle>Immunity</addtitle><date>1998-09-01</date><risdate>1998</risdate><volume>9</volume><issue>3</issue><spage>367</spage><epage>376</epage><pages>367-376</pages><issn>1074-7613</issn><eissn>1097-4180</eissn><abstract>The DNA-dependent protein kinase (DNA-PK) consists of Ku70, Ku80, and a large catalytic subunit, DNA-PKcs. Targeted inactivation of the Ku70 or Ku80 genes results in elevated ionizing radiation (IR) sensitivity and inability to perform both V(D)J coding-end and signal (RS)-end joining in cells, with severe growth retardation plus immunodeficiency in mice. In contrast, we now demonstrate that DNA-PKcs-null mice generated by gene-targeted mutation, while also severely immunodeficient, exhibit no growth retardation. Furthermore, DNA-PKcs-null cells are blocked for V(D)J coding-end joining, but retain normal RS-end joining. Finally, while DNA-PK-null fibroblasts exhibited increased IR sensitivity, DNA-PKcs-deficient ES cells did not. We conclude that Ku70 and Ku80 may have functions in V(D)J recombination and DNA repair that are independent of DNA-PKcs.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>9768756</pmid><doi>10.1016/S1074-7613(00)80619-6</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, Nuclear DNA Helicases DNA-Activated Protein Kinase DNA-Binding Proteins - physiology Embryo, Mammalian Female Fibroblasts - enzymology Fibroblasts - radiation effects Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics Gene Targeting Immunoglobulin Joining Region - genetics Ku Autoantigen Male Mice Mice, Inbred C57BL Mice, Knockout Mutation - genetics Nuclear Proteins - physiology Phenotype Protein-Serine-Threonine Kinases - biosynthesis Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - physiology Radiation, Ionizing Severe Combined Immunodeficiency - genetics Signal Transduction Stem Cells - enzymology Stem Cells - metabolism Stem Cells - physiology Stem Cells - radiation effects Thymus Gland - cytology Thymus Gland - physiology |
| title | A Targeted DNA-PKcs-Null Mutation Reveals DNA-PK-Independent Functions for KU in V(D)J Recombination |
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