hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response
Mutations in the BRCA1 (ref. 1 ) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer 2 , 3 . Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage r...
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| Veröffentlicht in: | Nature (London) 2000-03, Vol.404 (6774), p.201-204 |
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| creator | Lee, Jong-Soo Collins, Kimberly M. Brown, Alexandra L. Lee, Chang-Hun Chung, Jay H. |
| description | Mutations in the
BRCA1
(ref.
1
) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer
2
,
3
. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair
4
,
5
,
6
,
7
and cell-cycle checkpoint
8
,
9
,
10
. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage
11
,
12
. It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family
13
,
14
,
15
,
16
,
17
,
18
,
19
,
20
. Here we report that the human Cds1 kinase (hCds1/Chk2)
21
,
22
,
23
regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937. |
| doi_str_mv | 10.1038/35004614 |
| format | Article |
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BRCA1
(ref.
1
) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer
2
,
3
. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair
4
,
5
,
6
,
7
and cell-cycle checkpoint
8
,
9
,
10
. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage
11
,
12
. It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family
13
,
14
,
15
,
16
,
17
,
18
,
19
,
20
. Here we report that the human Cds1 kinase (hCds1/Chk2)
21
,
22
,
23
regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/35004614</identifier><identifier>PMID: 10724175</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Amino Acid Sequence ; Animals ; Biological and medical sciences ; BRCA1 protein ; BRCA1 Protein - genetics ; BRCA1 Protein - metabolism ; Cds1 kinase ; Cell Line ; Cell Nucleus - metabolism ; Checkpoint Kinase 2 ; DNA Damage ; Gamma Rays ; Genes, Tumor Suppressor ; Gynecology. Andrology. Obstetrics ; Humanities and Social Sciences ; Humans ; letter ; Mammary gland diseases ; Medical sciences ; Molecular Sequence Data ; multidisciplinary ; Phosphorylation ; Precipitin Tests ; Protein Binding - radiation effects ; Protein Kinases - metabolism ; Protein-Serine-Threonine Kinases ; Recombinant Fusion Proteins - metabolism ; Science ; Science (multidisciplinary) ; Serine - metabolism ; Tumors</subject><ispartof>Nature (London), 2000-03, Vol.404 (6774), p.201-204</ispartof><rights>Macmillan Magazines Ltd. 2000</rights><rights>2000 INIST-CNRS</rights><rights>COPYRIGHT 2000 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c613t-9798ea4fd84eed6fb544abc10db61dcbcb289c1d9249d69b9e71e1be22258de73</citedby><cites>FETCH-LOGICAL-c613t-9798ea4fd84eed6fb544abc10db61dcbcb289c1d9249d69b9e71e1be22258de73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/35004614$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/35004614$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1347836$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10724175$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Jong-Soo</creatorcontrib><creatorcontrib>Collins, Kimberly M.</creatorcontrib><creatorcontrib>Brown, Alexandra L.</creatorcontrib><creatorcontrib>Lee, Chang-Hun</creatorcontrib><creatorcontrib>Chung, Jay H.</creatorcontrib><title>hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Mutations in the
BRCA1
(ref.
1
) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer
2
,
3
. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair
4
,
5
,
6
,
7
and cell-cycle checkpoint
8
,
9
,
10
. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage
11
,
12
. It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family
13
,
14
,
15
,
16
,
17
,
18
,
19
,
20
. Here we report that the human Cds1 kinase (hCds1/Chk2)
21
,
22
,
23
regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>BRCA1 protein</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA1 Protein - metabolism</subject><subject>Cds1 kinase</subject><subject>Cell Line</subject><subject>Cell Nucleus - metabolism</subject><subject>Checkpoint Kinase 2</subject><subject>DNA Damage</subject><subject>Gamma Rays</subject><subject>Genes, Tumor Suppressor</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>letter</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>multidisciplinary</subject><subject>Phosphorylation</subject><subject>Precipitin Tests</subject><subject>Protein Binding - radiation effects</subject><subject>Protein Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Serine - metabolism</subject><subject>Tumors</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0m1r1TAUB_Agirubgp9AigxRpDOnTZv0Za1PF8aEOfFlSJPT3o626ZIWtm9v5F7ZLl6REALJLwnn8CfkBdAzoKl4n2aUshzYI7ICxvOY5YI_JitKExFTkeZH5Nj7a0ppBpw9JUdAecKAZyuy3lTGQzyg6dSMJpo21ofp7no1d3aMbBN9uKxKiBy2S9hDH80bjD5elJFRg2oxHPjJjh6fkSeN6j0-360n5MfnT1fV1_j825d1VZ7HOod0jgteCFSsMYIhmrypM8ZUrYGaOgeja10notBgioQVJi_qAjkg1JgkSSYM8vSEvN6-Ozl7s6Cf5dB5jX2vRrSLl5wWofqM_ReGVogUsiTAeAtb1aPsxsbOTukWR3SqtyM2XdguQQiAJC-y4F8d8HrqbuRDdHYAhWFw6PTBV9_uXQhmxtu5VYv3cv39ct---7ctr35WF_v6zVZrZ7132MjJdYNydxKo_J0f-Sc_gb7c9WypQyYewG1gAjjdAeW16hunRt35e5cyHvJ2X4wPJ2OLTl7bxY0hF3__-Qto0dQC</recordid><startdate>20000309</startdate><enddate>20000309</enddate><creator>Lee, Jong-Soo</creator><creator>Collins, Kimberly M.</creator><creator>Brown, Alexandra L.</creator><creator>Lee, Chang-Hun</creator><creator>Chung, Jay H.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</general><scope>IQODW</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>ATWCN</scope><scope>7TM</scope><scope>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20000309</creationdate><title>hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response</title><author>Lee, Jong-Soo ; Collins, Kimberly M. ; Brown, Alexandra L. ; Lee, Chang-Hun ; Chung, Jay H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c613t-9798ea4fd84eed6fb544abc10db61dcbcb289c1d9249d69b9e71e1be22258de73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>BRCA1 protein</topic><topic>BRCA1 Protein - genetics</topic><topic>BRCA1 Protein - metabolism</topic><topic>Cds1 kinase</topic><topic>Cell Line</topic><topic>Cell Nucleus - metabolism</topic><topic>Checkpoint Kinase 2</topic><topic>DNA Damage</topic><topic>Gamma Rays</topic><topic>Genes, Tumor Suppressor</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>letter</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>multidisciplinary</topic><topic>Phosphorylation</topic><topic>Precipitin Tests</topic><topic>Protein Binding - radiation effects</topic><topic>Protein Kinases - metabolism</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Serine - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Jong-Soo</creatorcontrib><creatorcontrib>Collins, Kimberly M.</creatorcontrib><creatorcontrib>Brown, Alexandra L.</creatorcontrib><creatorcontrib>Lee, Chang-Hun</creatorcontrib><creatorcontrib>Chung, Jay H.</creatorcontrib><collection>Pascal-Francis</collection><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: Middle School</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Jong-Soo</au><au>Collins, Kimberly M.</au><au>Brown, Alexandra L.</au><au>Lee, Chang-Hun</au><au>Chung, Jay H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2000-03-09</date><risdate>2000</risdate><volume>404</volume><issue>6774</issue><spage>201</spage><epage>204</epage><pages>201-204</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>Mutations in the
BRCA1
(ref.
1
) tumour suppressor gene are found in almost all of the families with inherited breast and ovarian cancers and about half of the families with only breast cancer
2
,
3
. Although the biochemical function of BRCA1 is not well understood, it is important for DNA damage repair
4
,
5
,
6
,
7
and cell-cycle checkpoint
8
,
9
,
10
. BRCA1 exists in nuclear foci but is hyperphosphorylated and disperses after DNA damage
11
,
12
. It is not known whether BRCA1 phosphorylation and dispersion and its function in DNA damage response are related. In yeast the DNA damage response and the replication-block checkpoint are mediated partly through the Cds1 kinase family
13
,
14
,
15
,
16
,
17
,
18
,
19
,
20
. Here we report that the human Cds1 kinase (hCds1/Chk2)
21
,
22
,
23
regulates BRCA1 function after DNA damage by phosphorylating serine 988 of BRCA1. We show that hCds1 and BRCA1 interact and co-localize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>10724175</pmid><doi>10.1038/35004614</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Nature (London), 2000-03, Vol.404 (6774), p.201-204 |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | Amino Acid Sequence Animals Biological and medical sciences BRCA1 protein BRCA1 Protein - genetics BRCA1 Protein - metabolism Cds1 kinase Cell Line Cell Nucleus - metabolism Checkpoint Kinase 2 DNA Damage Gamma Rays Genes, Tumor Suppressor Gynecology. Andrology. Obstetrics Humanities and Social Sciences Humans letter Mammary gland diseases Medical sciences Molecular Sequence Data multidisciplinary Phosphorylation Precipitin Tests Protein Binding - radiation effects Protein Kinases - metabolism Protein-Serine-Threonine Kinases Recombinant Fusion Proteins - metabolism Science Science (multidisciplinary) Serine - metabolism Tumors |
| title | hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response |
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