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Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1
DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogas...
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| Published in: | Human molecular genetics 2014-03, Vol.23 (5), p.1345-1364 |
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| cites | cdi_FETCH-LOGICAL-c356t-91d1d8757f51f45e9c0e1d318cdea99799f2fbeb61c70b425b4dcf8a4aeb00ca3 |
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| container_title | Human molecular genetics |
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| creator | Barclay, Sam S Tamura, Takuya Ito, Hikaru Fujita, Kyota Tagawa, Kazuhiko Shimamura, Teppei Katsuta, Asuka Shiwaku, Hiroki Sone, Masaki Imoto, Seiya Miyano, Satoru Okazawa, Hitoshi |
| description | DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR. |
| doi_str_mv | 10.1093/hmg/ddt524 |
| format | article |
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In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddt524</identifier><identifier>PMID: 24179173</identifier><language>eng</language><publisher>England</publisher><subject>Animals ; Animals, Genetically Modified ; Ataxin-1 ; Ataxins ; Cell Cycle - genetics ; Checkpoint Kinase 1 ; Disease Models, Animal ; DNA Damage ; DNA Repair ; Drosophila - genetics ; Drosophila melanogaster ; Female ; Gene Regulatory Networks ; Genetic Vectors - genetics ; Humans ; Longevity - genetics ; Male ; Mutagenesis, Insertional ; Mutation ; Nerve Tissue Proteins - genetics ; Nuclear Proteins - genetics ; Protein Kinases - metabolism ; Purkinje Cells - metabolism ; Signal Transduction ; Spinocerebellar Ataxias - genetics ; Spinocerebellar Ataxias - metabolism ; Spinocerebellar Ataxias - mortality ; Systems Biology</subject><ispartof>Human molecular genetics, 2014-03, Vol.23 (5), p.1345-1364</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-91d1d8757f51f45e9c0e1d318cdea99799f2fbeb61c70b425b4dcf8a4aeb00ca3</citedby><cites>FETCH-LOGICAL-c356t-91d1d8757f51f45e9c0e1d318cdea99799f2fbeb61c70b425b4dcf8a4aeb00ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24179173$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barclay, Sam S</creatorcontrib><creatorcontrib>Tamura, Takuya</creatorcontrib><creatorcontrib>Ito, Hikaru</creatorcontrib><creatorcontrib>Fujita, Kyota</creatorcontrib><creatorcontrib>Tagawa, Kazuhiko</creatorcontrib><creatorcontrib>Shimamura, Teppei</creatorcontrib><creatorcontrib>Katsuta, Asuka</creatorcontrib><creatorcontrib>Shiwaku, Hiroki</creatorcontrib><creatorcontrib>Sone, Masaki</creatorcontrib><creatorcontrib>Imoto, Seiya</creatorcontrib><creatorcontrib>Miyano, Satoru</creatorcontrib><creatorcontrib>Okazawa, Hitoshi</creatorcontrib><title>Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.</description><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Ataxin-1</subject><subject>Ataxins</subject><subject>Cell Cycle - genetics</subject><subject>Checkpoint Kinase 1</subject><subject>Disease Models, Animal</subject><subject>DNA Damage</subject><subject>DNA Repair</subject><subject>Drosophila - genetics</subject><subject>Drosophila melanogaster</subject><subject>Female</subject><subject>Gene Regulatory Networks</subject><subject>Genetic Vectors - genetics</subject><subject>Humans</subject><subject>Longevity - genetics</subject><subject>Male</subject><subject>Mutagenesis, Insertional</subject><subject>Mutation</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nuclear Proteins - genetics</subject><subject>Protein Kinases - metabolism</subject><subject>Purkinje Cells - metabolism</subject><subject>Signal Transduction</subject><subject>Spinocerebellar Ataxias - genetics</subject><subject>Spinocerebellar Ataxias - metabolism</subject><subject>Spinocerebellar Ataxias - mortality</subject><subject>Systems Biology</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqFkU9PwjAYhxujEUQvfgDTozGZtGu70SMB_yVED-h56dq3UN1WaAeGb-8I6NXT-x6ePIffg9A1JfeUSDZc1ouhMa1I-QnqU56RJCUjdor6RGY8ySTJeugixk9CaMZZfo56Kae5pDnro_V8F1uoIy6dr_xih1Wjql10EXuLp8FHv1q6SmHX4K3behx1AGiwUa3CUG206z6IWPsAuIH224eviK0PePo67qhaLQAHWCkX9or5ZEwv0ZlVVYSr4x2gj8eH98lzMnt7epmMZ4lmImsTSQ01o1zkVlDLBUhNgBpGR9qAkjKX0qa2hDKjOiclT0XJjbYjxRWUhGjFBuj24F0Fv95AbIvaRQ1VpRrwm1hQQQQThKX5_yiXkjLGUtKhdwdUd9vEALZYBVersCsoKfY1iq5GcajRwTdH76aswfyhv_OzH4ODhx4</recordid><startdate>20140301</startdate><enddate>20140301</enddate><creator>Barclay, Sam S</creator><creator>Tamura, Takuya</creator><creator>Ito, Hikaru</creator><creator>Fujita, Kyota</creator><creator>Tagawa, Kazuhiko</creator><creator>Shimamura, Teppei</creator><creator>Katsuta, Asuka</creator><creator>Shiwaku, Hiroki</creator><creator>Sone, Masaki</creator><creator>Imoto, Seiya</creator><creator>Miyano, Satoru</creator><creator>Okazawa, Hitoshi</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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20140301</creationdate><title>Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1</title><author>Barclay, Sam S ; Tamura, Takuya ; Ito, Hikaru ; Fujita, Kyota ; Tagawa, Kazuhiko ; Shimamura, Teppei ; Katsuta, Asuka ; Shiwaku, Hiroki ; Sone, Masaki ; Imoto, Seiya ; Miyano, Satoru ; Okazawa, Hitoshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-91d1d8757f51f45e9c0e1d318cdea99799f2fbeb61c70b425b4dcf8a4aeb00ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Ataxin-1</topic><topic>Ataxins</topic><topic>Cell Cycle - genetics</topic><topic>Checkpoint Kinase 1</topic><topic>Disease Models, Animal</topic><topic>DNA Damage</topic><topic>DNA Repair</topic><topic>Drosophila - genetics</topic><topic>Drosophila melanogaster</topic><topic>Female</topic><topic>Gene Regulatory Networks</topic><topic>Genetic Vectors - genetics</topic><topic>Humans</topic><topic>Longevity - genetics</topic><topic>Male</topic><topic>Mutagenesis, Insertional</topic><topic>Mutation</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nuclear Proteins - genetics</topic><topic>Protein Kinases - metabolism</topic><topic>Purkinje Cells - metabolism</topic><topic>Signal Transduction</topic><topic>Spinocerebellar Ataxias - genetics</topic><topic>Spinocerebellar Ataxias - metabolism</topic><topic>Spinocerebellar Ataxias - mortality</topic><topic>Systems Biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barclay, Sam S</creatorcontrib><creatorcontrib>Tamura, Takuya</creatorcontrib><creatorcontrib>Ito, Hikaru</creatorcontrib><creatorcontrib>Fujita, Kyota</creatorcontrib><creatorcontrib>Tagawa, Kazuhiko</creatorcontrib><creatorcontrib>Shimamura, Teppei</creatorcontrib><creatorcontrib>Katsuta, Asuka</creatorcontrib><creatorcontrib>Shiwaku, Hiroki</creatorcontrib><creatorcontrib>Sone, Masaki</creatorcontrib><creatorcontrib>Imoto, Seiya</creatorcontrib><creatorcontrib>Miyano, Satoru</creatorcontrib><creatorcontrib>Okazawa, Hitoshi</creatorcontrib><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>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barclay, Sam S</au><au>Tamura, Takuya</au><au>Ito, Hikaru</au><au>Fujita, Kyota</au><au>Tagawa, Kazuhiko</au><au>Shimamura, Teppei</au><au>Katsuta, Asuka</au><au>Shiwaku, Hiroki</au><au>Sone, Masaki</au><au>Imoto, Seiya</au><au>Miyano, Satoru</au><au>Okazawa, Hitoshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2014-03-01</date><risdate>2014</risdate><volume>23</volume><issue>5</issue><spage>1345</spage><epage>1364</epage><pages>1345-1364</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>ObjectType-Article-2</notes><notes>ObjectType-Feature-1</notes><abstract>DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.</abstract><cop>England</cop><pmid>24179173</pmid><doi>10.1093/hmg/ddt524</doi><tpages>20</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Human molecular genetics, 2014-03, Vol.23 (5), p.1345-1364 |
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| source | OUP_牛津大学出版社现刊 |
| subjects | Animals Animals, Genetically Modified Ataxin-1 Ataxins Cell Cycle - genetics Checkpoint Kinase 1 Disease Models, Animal DNA Damage DNA Repair Drosophila - genetics Drosophila melanogaster Female Gene Regulatory Networks Genetic Vectors - genetics Humans Longevity - genetics Male Mutagenesis, Insertional Mutation Nerve Tissue Proteins - genetics Nuclear Proteins - genetics Protein Kinases - metabolism Purkinje Cells - metabolism Signal Transduction Spinocerebellar Ataxias - genetics Spinocerebellar Ataxias - metabolism Spinocerebellar Ataxias - mortality Systems Biology |
| title | Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1 |
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