Shugoshin 1 is dislocated by KSHV-encoded LANA inducing aneuploidy
Shugoshin-1 (Sgo1) protects the integrity of the centromeres, and H2A phosphorylation is critical for this process. The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromoso...
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| creator | Lang, Fengchao Sun, Zhiguo Pei, Yonggang Singh, Rajnish Kumar Jha, Hem Chandra Robertson, Erle S |
| description | Shugoshin-1 (Sgo1) protects the integrity of the centromeres, and H2A phosphorylation is critical for this process. The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromosomal instability (CIN), and its essential antigen LANA regulates Bub1. We show that LANA inhibits Bub1 phosphorylation of H2A and Cdc20, important for chromosome segregation and mitotic signaling. Inhibition of H2A phosphorylation at residue T120 by LANA resulted in dislocation of Sgo1, and cohesin from the centromeres. Arrest of Cdc20 phosphorylation also rescued degradation of Securin and Cyclin B1 at mitotic exit, and interaction of H2A, and Cdc20 with Bub1 was inhibited by LANA. The N-terminal nuclear localization sequence domain of LANA was essential for LANA and Bub1 interaction, reversed LANA inhibited phosphorylation of H2A and Cdc20, and attenuated LANA-induced aneuploidy and cell proliferation. This molecular mechanism whereby KSHV-induced CIN, demonstrated that the NNLS of LANA is a promising target for development of anti-viral therapies targeting KSHV associated cancers. |
| doi_str_mv | 10.1371/journal.ppat.1007253 |
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The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromosomal instability (CIN), and its essential antigen LANA regulates Bub1. We show that LANA inhibits Bub1 phosphorylation of H2A and Cdc20, important for chromosome segregation and mitotic signaling. Inhibition of H2A phosphorylation at residue T120 by LANA resulted in dislocation of Sgo1, and cohesin from the centromeres. Arrest of Cdc20 phosphorylation also rescued degradation of Securin and Cyclin B1 at mitotic exit, and interaction of H2A, and Cdc20 with Bub1 was inhibited by LANA. The N-terminal nuclear localization sequence domain of LANA was essential for LANA and Bub1 interaction, reversed LANA inhibited phosphorylation of H2A and Cdc20, and attenuated LANA-induced aneuploidy and cell proliferation. This molecular mechanism whereby KSHV-induced CIN, demonstrated that the NNLS of LANA is a promising target for development of anti-viral therapies targeting KSHV associated cancers.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1007253</identifier><identifier>PMID: 30212568</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aneuploidy ; Antigens ; Antiviral agents ; Biology and Life Sciences ; Biomedical engineering ; Cancer ; Cell cycle ; Cell division ; Cell proliferation ; Centromeres ; Chromosome number ; Chromosomes ; Cohesin ; Cyclin B1 ; Dislocation ; Dislocations ; Dosage and administration ; Drug resistance ; Drug therapy ; Genetic aspects ; Genetic engineering ; Genomes ; Genomic instability ; Health aspects ; Infections ; Kaposi's sarcoma ; Kinases ; Localization ; Lymphoma ; Medicine ; Otolaryngology ; Phosphorylation ; Proteins ; Research and Analysis Methods ; Securin ; Stability ; Surgery ; Tumorigenesis ; Virology</subject><ispartof>PLoS pathogens, 2018-09, Vol.14 (9), p.e1007253-e1007253</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Lang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Lang et al 2018 Lang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c661t-482206d1f53ae45f8fcc30a68420430c02ab5bd3960f0542aad52348eb3a2ea73</citedby><cites>FETCH-LOGICAL-c661t-482206d1f53ae45f8fcc30a68420430c02ab5bd3960f0542aad52348eb3a2ea73</cites><orcidid>0000-0001-7296-8772</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136811/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136811/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30212568$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lang, Fengchao</creatorcontrib><creatorcontrib>Sun, Zhiguo</creatorcontrib><creatorcontrib>Pei, Yonggang</creatorcontrib><creatorcontrib>Singh, Rajnish Kumar</creatorcontrib><creatorcontrib>Jha, Hem Chandra</creatorcontrib><creatorcontrib>Robertson, Erle S</creatorcontrib><title>Shugoshin 1 is dislocated by KSHV-encoded LANA inducing aneuploidy</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>Shugoshin-1 (Sgo1) protects the integrity of the centromeres, and H2A phosphorylation is critical for this process. The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromosomal instability (CIN), and its essential antigen LANA regulates Bub1. We show that LANA inhibits Bub1 phosphorylation of H2A and Cdc20, important for chromosome segregation and mitotic signaling. Inhibition of H2A phosphorylation at residue T120 by LANA resulted in dislocation of Sgo1, and cohesin from the centromeres. Arrest of Cdc20 phosphorylation also rescued degradation of Securin and Cyclin B1 at mitotic exit, and interaction of H2A, and Cdc20 with Bub1 was inhibited by LANA. The N-terminal nuclear localization sequence domain of LANA was essential for LANA and Bub1 interaction, reversed LANA inhibited phosphorylation of H2A and Cdc20, and attenuated LANA-induced aneuploidy and cell proliferation. This molecular mechanism whereby KSHV-induced CIN, demonstrated that the NNLS of LANA is a promising target for development of anti-viral therapies targeting KSHV associated cancers.</description><subject>Aneuploidy</subject><subject>Antigens</subject><subject>Antiviral agents</subject><subject>Biology and Life Sciences</subject><subject>Biomedical engineering</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell division</subject><subject>Cell proliferation</subject><subject>Centromeres</subject><subject>Chromosome number</subject><subject>Chromosomes</subject><subject>Cohesin</subject><subject>Cyclin B1</subject><subject>Dislocation</subject><subject>Dislocations</subject><subject>Dosage and administration</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Genomes</subject><subject>Genomic instability</subject><subject>Health 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aspects</topic><topic>Genetic engineering</topic><topic>Genomes</topic><topic>Genomic instability</topic><topic>Health aspects</topic><topic>Infections</topic><topic>Kaposi's sarcoma</topic><topic>Kinases</topic><topic>Localization</topic><topic>Lymphoma</topic><topic>Medicine</topic><topic>Otolaryngology</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Securin</topic><topic>Stability</topic><topic>Surgery</topic><topic>Tumorigenesis</topic><topic>Virology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lang, Fengchao</creatorcontrib><creatorcontrib>Sun, Zhiguo</creatorcontrib><creatorcontrib>Pei, Yonggang</creatorcontrib><creatorcontrib>Singh, Rajnish Kumar</creatorcontrib><creatorcontrib>Jha, Hem Chandra</creatorcontrib><creatorcontrib>Robertson, Erle S</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: 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Pathog</addtitle><date>2018-09-01</date><risdate>2018</risdate><volume>14</volume><issue>9</issue><spage>e1007253</spage><epage>e1007253</epage><pages>e1007253-e1007253</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Shugoshin-1 (Sgo1) protects the integrity of the centromeres, and H2A phosphorylation is critical for this process. The mitotic checkpoint kinase Bub1, phosphorylates H2A and ensures fidelity of chromosome segregation and chromosome number. Oncogenic KSHV induces genetic alterations through chromosomal instability (CIN), and its essential antigen LANA regulates Bub1. We show that LANA inhibits Bub1 phosphorylation of H2A and Cdc20, important for chromosome segregation and mitotic signaling. Inhibition of H2A phosphorylation at residue T120 by LANA resulted in dislocation of Sgo1, and cohesin from the centromeres. Arrest of Cdc20 phosphorylation also rescued degradation of Securin and Cyclin B1 at mitotic exit, and interaction of H2A, and Cdc20 with Bub1 was inhibited by LANA. The N-terminal nuclear localization sequence domain of LANA was essential for LANA and Bub1 interaction, reversed LANA inhibited phosphorylation of H2A and Cdc20, and attenuated LANA-induced aneuploidy and cell proliferation. This molecular mechanism whereby KSHV-induced CIN, demonstrated that the NNLS of LANA is a promising target for development of anti-viral therapies targeting KSHV associated cancers.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30212568</pmid><doi>10.1371/journal.ppat.1007253</doi><orcidid>https://orcid.org/0000-0001-7296-8772</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aneuploidy Antigens Antiviral agents Biology and Life Sciences Biomedical engineering Cancer Cell cycle Cell division Cell proliferation Centromeres Chromosome number Chromosomes Cohesin Cyclin B1 Dislocation Dislocations Dosage and administration Drug resistance Drug therapy Genetic aspects Genetic engineering Genomes Genomic instability Health aspects Infections Kaposi's sarcoma Kinases Localization Lymphoma Medicine Otolaryngology Phosphorylation Proteins Research and Analysis Methods Securin Stability Surgery Tumorigenesis Virology |
| title | Shugoshin 1 is dislocated by KSHV-encoded LANA inducing aneuploidy |
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