Fanconi anemia signaling network regulates the spindle assembly checkpoint
Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role...
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| Veröffentlicht in: | The Journal of clinical investigation 2013-09, Vol.123 (9), p.3839-3847 |
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| container_title | The Journal of clinical investigation |
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| creator | Nalepa, Grzegorz Enzor, Rikki Sun, Zejin Marchal, Christophe Park, Su-Jung Yang, Yanzhu Tedeschi, Laura Kelich, Stephanie Hanenberg, Helmut Clapp, D Wade |
| description | Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway. |
| doi_str_mv | 10.1172/JCI67364 |
| format | Article |
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The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI67364</identifier><identifier>PMID: 23934222</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Aneuploidy ; Antigens - metabolism ; Biomedical research ; Cancer ; Cell cycle ; Cell division ; Cell Nucleus - metabolism ; Centrosome - metabolism ; Chromosomes ; Development and progression ; Experiments ; Fanconi Anemia - genetics ; Fanconi Anemia - metabolism ; Fanconi Anemia - pathology ; Fanconi Anemia Complementation Group Proteins - genetics ; Fanconi Anemia Complementation Group Proteins - metabolism ; Fanconi's anemia ; Fibroblasts - physiology ; Flow cytometry ; Gene Knockdown Techniques ; Genes ; HeLa Cells ; Humans ; Hypotheses ; M Phase Cell Cycle Checkpoints ; Microscopy ; Mitosis ; Mutation ; Patients ; Proteins ; Risk factors ; RNA Interference ; RNA, Small Interfering - genetics ; Signal Transduction ; Spindle Apparatus - metabolism ; Studies</subject><ispartof>The Journal of clinical investigation, 2013-09, Vol.123 (9), p.3839-3847</ispartof><rights>COPYRIGHT 2013 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Sep 2013</rights><rights>Copyright © 2013, American Society for Clinical Investigation 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c703t-c45aaf3bc0777203b9ba9f08ad344713871df2a635f62d3476347121c6e3e33</citedby><cites>FETCH-LOGICAL-c703t-c45aaf3bc0777203b9ba9f08ad344713871df2a635f62d3476347121c6e3e33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754252/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754252/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23934222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nalepa, Grzegorz</creatorcontrib><creatorcontrib>Enzor, Rikki</creatorcontrib><creatorcontrib>Sun, Zejin</creatorcontrib><creatorcontrib>Marchal, Christophe</creatorcontrib><creatorcontrib>Park, Su-Jung</creatorcontrib><creatorcontrib>Yang, Yanzhu</creatorcontrib><creatorcontrib>Tedeschi, Laura</creatorcontrib><creatorcontrib>Kelich, Stephanie</creatorcontrib><creatorcontrib>Hanenberg, Helmut</creatorcontrib><creatorcontrib>Clapp, D Wade</creatorcontrib><title>Fanconi anemia signaling network regulates the spindle assembly checkpoint</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.</description><subject>Aneuploidy</subject><subject>Antigens - metabolism</subject><subject>Biomedical research</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell division</subject><subject>Cell Nucleus - metabolism</subject><subject>Centrosome - metabolism</subject><subject>Chromosomes</subject><subject>Development and progression</subject><subject>Experiments</subject><subject>Fanconi Anemia - genetics</subject><subject>Fanconi Anemia - metabolism</subject><subject>Fanconi Anemia - pathology</subject><subject>Fanconi Anemia Complementation Group Proteins - genetics</subject><subject>Fanconi Anemia Complementation Group Proteins - metabolism</subject><subject>Fanconi's anemia</subject><subject>Fibroblasts - physiology</subject><subject>Flow cytometry</subject><subject>Gene Knockdown Techniques</subject><subject>Genes</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>M Phase Cell Cycle Checkpoints</subject><subject>Microscopy</subject><subject>Mitosis</subject><subject>Mutation</subject><subject>Patients</subject><subject>Proteins</subject><subject>Risk factors</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - 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The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy. Furthermore, we discovered that FA proteins differentially localize to key structures of the mitotic apparatus in a cell cycle-dependent manner. The essential role of the FA pathway in mitosis offers a mechanistic explanation for the aneuploidy and malignant transformation known to occur after disruption of FA signaling. Collectively, our findings provide insight into the genetically unstable cancers resulting from inactivation of the FA/BRCA pathway.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>23934222</pmid><doi>10.1172/JCI67364</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Aneuploidy Antigens - metabolism Biomedical research Cancer Cell cycle Cell division Cell Nucleus - metabolism Centrosome - metabolism Chromosomes Development and progression Experiments Fanconi Anemia - genetics Fanconi Anemia - metabolism Fanconi Anemia - pathology Fanconi Anemia Complementation Group Proteins - genetics Fanconi Anemia Complementation Group Proteins - metabolism Fanconi's anemia Fibroblasts - physiology Flow cytometry Gene Knockdown Techniques Genes HeLa Cells Humans Hypotheses M Phase Cell Cycle Checkpoints Microscopy Mitosis Mutation Patients Proteins Risk factors RNA Interference RNA, Small Interfering - genetics Signal Transduction Spindle Apparatus - metabolism Studies |
| title | Fanconi anemia signaling network regulates the spindle assembly checkpoint |
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