Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania
Abstract Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCr...
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| Veröffentlicht in: | Nucleic acids research 2018-12, Vol.46 (22), p.11835-11846 |
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| creator | Damasceno, Jeziel D Obonaga, Ricardo Silva, Gabriel L A Reis-Cunha, João L Duncan, Samuel M Bartholomeu, Daniella C Mottram, Jeremy C McCulloch, Richard Tosi, Luiz R O |
| description | Abstract
Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCre-mediated conditional gene deletion to show that HUS1, a component of the 9-1-1 (RAD9-RAD1-HUS1) complex, is essential and is required for a G2/M checkpoint. By analyzing genome-wide instability in HUS1 ablated cells, HUS1 is shown to have a conserved role, by which it preserves genome stability and also a divergent role, by which it promotes genome variability. These roles of HUS1 are related to distinct patterns of formation and resolution of single-stranded DNA and γH2A, throughout the cell cycle. Our findings suggest that Leishmania 9-1-1 subunits have evolved to co-opt canonical genomic maintenance and genomic variation functions. Hence, this study reveals a pivotal function of HUS1 in balancing genome stability and transmission in Leishmania. These findings may be relevant to understanding the evolution of genome maintenance and plasticity in other pathogens and eukaryotes. |
| doi_str_mv | 10.1093/nar/gky1017 |
| format | Article |
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Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCre-mediated conditional gene deletion to show that HUS1, a component of the 9-1-1 (RAD9-RAD1-HUS1) complex, is essential and is required for a G2/M checkpoint. By analyzing genome-wide instability in HUS1 ablated cells, HUS1 is shown to have a conserved role, by which it preserves genome stability and also a divergent role, by which it promotes genome variability. These roles of HUS1 are related to distinct patterns of formation and resolution of single-stranded DNA and γH2A, throughout the cell cycle. Our findings suggest that Leishmania 9-1-1 subunits have evolved to co-opt canonical genomic maintenance and genomic variation functions. Hence, this study reveals a pivotal function of HUS1 in balancing genome stability and transmission in Leishmania. These findings may be relevant to understanding the evolution of genome maintenance and plasticity in other pathogens and eukaryotes.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gky1017</identifier><identifier>PMID: 30380080</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Cell Cycle Proteins - deficiency ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Computational Biology - methods ; Culture Media - chemistry ; DNA Repair Enzymes - genetics ; DNA Repair Enzymes - metabolism ; DNA, Single-Stranded - genetics ; DNA, Single-Stranded - metabolism ; Endonucleases - genetics ; Endonucleases - metabolism ; G2 Phase Cell Cycle Checkpoints - genetics ; Gene Deletion ; Gene Expression Regulation ; Genetic Engineering ; Genetic Variation ; Genome Integrity, Repair and ; Genome, Protozoan ; Genomic Instability ; Histones - genetics ; Histones - metabolism ; Leishmania major - genetics ; Leishmania major - metabolism ; Whole Genome Sequencing</subject><ispartof>Nucleic acids research, 2018-12, Vol.46 (22), p.11835-11846</ispartof><rights>The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-8bd9e2321d4c36e5dd57222fbdfa121977ac04f6fc03725c169ce234448816713</citedby><cites>FETCH-LOGICAL-c375t-8bd9e2321d4c36e5dd57222fbdfa121977ac04f6fc03725c169ce234448816713</cites><orcidid>0000-0001-5739-976X</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/PMC6294564/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294564/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,1586,1606,27931,27932,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30380080$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Damasceno, Jeziel D</creatorcontrib><creatorcontrib>Obonaga, Ricardo</creatorcontrib><creatorcontrib>Silva, Gabriel L A</creatorcontrib><creatorcontrib>Reis-Cunha, João L</creatorcontrib><creatorcontrib>Duncan, Samuel M</creatorcontrib><creatorcontrib>Bartholomeu, Daniella C</creatorcontrib><creatorcontrib>Mottram, Jeremy C</creatorcontrib><creatorcontrib>McCulloch, Richard</creatorcontrib><creatorcontrib>Tosi, Luiz R O</creatorcontrib><title>Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCre-mediated conditional gene deletion to show that HUS1, a component of the 9-1-1 (RAD9-RAD1-HUS1) complex, is essential and is required for a G2/M checkpoint. By analyzing genome-wide instability in HUS1 ablated cells, HUS1 is shown to have a conserved role, by which it preserves genome stability and also a divergent role, by which it promotes genome variability. These roles of HUS1 are related to distinct patterns of formation and resolution of single-stranded DNA and γH2A, throughout the cell cycle. Our findings suggest that Leishmania 9-1-1 subunits have evolved to co-opt canonical genomic maintenance and genomic variation functions. Hence, this study reveals a pivotal function of HUS1 in balancing genome stability and transmission in Leishmania. These findings may be relevant to understanding the evolution of genome maintenance and plasticity in other pathogens and eukaryotes.</description><subject>Cell Cycle Proteins - deficiency</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Computational Biology - methods</subject><subject>Culture Media - chemistry</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA Repair Enzymes - metabolism</subject><subject>DNA, Single-Stranded - genetics</subject><subject>DNA, Single-Stranded - metabolism</subject><subject>Endonucleases - genetics</subject><subject>Endonucleases - metabolism</subject><subject>G2 Phase Cell Cycle Checkpoints - genetics</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation</subject><subject>Genetic Engineering</subject><subject>Genetic Variation</subject><subject>Genome Integrity, Repair and</subject><subject>Genome, Protozoan</subject><subject>Genomic Instability</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Leishmania major - genetics</subject><subject>Leishmania major - metabolism</subject><subject>Whole Genome Sequencing</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kU9vFDEMxSNERZeWE3eUExc0NE4y_y5IaAUUaSUu7XmUTTyzgRlnlMyu2k_E1yTtdiu4cLL0_POzrcfYWxAfQbTqiky8Gn7dg4D6BVuBqmSh20q-ZCuhRFmA0M05e53STyFAQ6lfsXMlVCNEI1bs9zqQ84sPZEY-IIUJOdLgCTF6GnjEA5oxcWsokLcZMuS48weMmV54DCMm3ofIlx3y630CbsM0B3pohv5RbQsojvKId9zTozgZTwuSIYsnbh5NWrw9nZHVDfq0mwx5c8nO-nwHvnmqF-z265eb9XWx-fHt-_rzprCqLpei2boWpZLgtFUVls6VtZSy37regIS2ro0Vuq96K1QtSwtVazOvtW4aqGpQF-zT0Xfebyd0Nr8RzdjN0U8m3nfB-O7fDvldN4RDV8lWl5XOBh-OBjaGlCL2z7Mguoe8upxX95RXpt_9ve6ZPQWUgfdHIOzn_zr9AbByong</recordid><startdate>20181214</startdate><enddate>20181214</enddate><creator>Damasceno, Jeziel D</creator><creator>Obonaga, Ricardo</creator><creator>Silva, Gabriel L A</creator><creator>Reis-Cunha, João L</creator><creator>Duncan, Samuel M</creator><creator>Bartholomeu, Daniella C</creator><creator>Mottram, Jeremy C</creator><creator>McCulloch, Richard</creator><creator>Tosi, Luiz R O</creator><general>Oxford University Press</general><scope>TOX</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>5PM</scope><orcidid>https://orcid.org/0000-0001-5739-976X</orcidid></search><sort><creationdate>20181214</creationdate><title>Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania</title><author>Damasceno, Jeziel D ; Obonaga, Ricardo ; Silva, Gabriel L A ; Reis-Cunha, João L ; Duncan, Samuel M ; Bartholomeu, Daniella C ; Mottram, Jeremy C ; McCulloch, Richard ; Tosi, Luiz R O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-8bd9e2321d4c36e5dd57222fbdfa121977ac04f6fc03725c169ce234448816713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Cell Cycle Proteins - deficiency</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Computational Biology - methods</topic><topic>Culture Media - chemistry</topic><topic>DNA Repair Enzymes - genetics</topic><topic>DNA Repair Enzymes - metabolism</topic><topic>DNA, Single-Stranded - genetics</topic><topic>DNA, Single-Stranded - metabolism</topic><topic>Endonucleases - genetics</topic><topic>Endonucleases - metabolism</topic><topic>G2 Phase Cell Cycle Checkpoints - genetics</topic><topic>Gene Deletion</topic><topic>Gene Expression Regulation</topic><topic>Genetic Engineering</topic><topic>Genetic Variation</topic><topic>Genome Integrity, Repair and</topic><topic>Genome, Protozoan</topic><topic>Genomic Instability</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Leishmania major - genetics</topic><topic>Leishmania major - metabolism</topic><topic>Whole Genome Sequencing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Damasceno, Jeziel D</creatorcontrib><creatorcontrib>Obonaga, Ricardo</creatorcontrib><creatorcontrib>Silva, Gabriel L A</creatorcontrib><creatorcontrib>Reis-Cunha, João L</creatorcontrib><creatorcontrib>Duncan, Samuel M</creatorcontrib><creatorcontrib>Bartholomeu, Daniella C</creatorcontrib><creatorcontrib>Mottram, Jeremy C</creatorcontrib><creatorcontrib>McCulloch, Richard</creatorcontrib><creatorcontrib>Tosi, Luiz R O</creatorcontrib><collection>Access via Oxford University Press (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Damasceno, Jeziel D</au><au>Obonaga, Ricardo</au><au>Silva, Gabriel L A</au><au>Reis-Cunha, João L</au><au>Duncan, Samuel M</au><au>Bartholomeu, Daniella C</au><au>Mottram, Jeremy C</au><au>McCulloch, Richard</au><au>Tosi, Luiz R O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2018-12-14</date><risdate>2018</risdate><volume>46</volume><issue>22</issue><spage>11835</spage><epage>11846</epage><pages>11835-11846</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCre-mediated conditional gene deletion to show that HUS1, a component of the 9-1-1 (RAD9-RAD1-HUS1) complex, is essential and is required for a G2/M checkpoint. By analyzing genome-wide instability in HUS1 ablated cells, HUS1 is shown to have a conserved role, by which it preserves genome stability and also a divergent role, by which it promotes genome variability. These roles of HUS1 are related to distinct patterns of formation and resolution of single-stranded DNA and γH2A, throughout the cell cycle. Our findings suggest that Leishmania 9-1-1 subunits have evolved to co-opt canonical genomic maintenance and genomic variation functions. Hence, this study reveals a pivotal function of HUS1 in balancing genome stability and transmission in Leishmania. These findings may be relevant to understanding the evolution of genome maintenance and plasticity in other pathogens and eukaryotes.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>30380080</pmid><doi>10.1093/nar/gky1017</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-5739-976X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Cell Cycle Proteins - deficiency Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Computational Biology - methods Culture Media - chemistry DNA Repair Enzymes - genetics DNA Repair Enzymes - metabolism DNA, Single-Stranded - genetics DNA, Single-Stranded - metabolism Endonucleases - genetics Endonucleases - metabolism G2 Phase Cell Cycle Checkpoints - genetics Gene Deletion Gene Expression Regulation Genetic Engineering Genetic Variation Genome Integrity, Repair and Genome, Protozoan Genomic Instability Histones - genetics Histones - metabolism Leishmania major - genetics Leishmania major - metabolism Whole Genome Sequencing |
| title | Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania |
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