Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis
Abstract Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs...
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| Veröffentlicht in: | Human molecular genetics 2023-02, Vol.32 (5), p.745-763 |
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| container_title | Human molecular genetics |
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| creator | Patil, Shalaka Deshpande, Shruti Sengupta, Kundan |
| description | Abstract
Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs and micronuclei, with chromosomes showing higher frequency of losses, being enriched within the micronucleus. Furthermore, doxycycline-induced conditional depletion of LBR significantly increased tumor volumes that form within the subcutaneous xenografts of mice. Of note, the tumor-derived primary cells recapitulated chromosomal losses and gains, revealing a novel role for LBR as a tumor suppressor. Co-immunoprecipitation of LBR uncovered an association of LBR with telomere-associated factors. Interestingly, qPCR array-based gene expression profiling showed a significant upregulation of telomere repeat-binding factor 1 (TRF1) upon LBR depletion. Remarkably, TRF1 knockdown in the background of LBR depletion maintains chromosomal stability, unraveling a novel mechanism involving LBR and TRF in the maintenance of chromosomal stability in colorectal cancer cells.
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| doi_str_mv | 10.1093/hmg/ddac235 |
| format | Article |
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Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs and micronuclei, with chromosomes showing higher frequency of losses, being enriched within the micronucleus. Furthermore, doxycycline-induced conditional depletion of LBR significantly increased tumor volumes that form within the subcutaneous xenografts of mice. Of note, the tumor-derived primary cells recapitulated chromosomal losses and gains, revealing a novel role for LBR as a tumor suppressor. Co-immunoprecipitation of LBR uncovered an association of LBR with telomere-associated factors. Interestingly, qPCR array-based gene expression profiling showed a significant upregulation of telomere repeat-binding factor 1 (TRF1) upon LBR depletion. Remarkably, TRF1 knockdown in the background of LBR depletion maintains chromosomal stability, unraveling a novel mechanism involving LBR and TRF in the maintenance of chromosomal stability in colorectal cancer cells.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddac235</identifier><identifier>PMID: 36124691</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Carcinogenesis ; Chromosomal Instability ; Humans ; Lamin B Receptor ; Lamin Type B - metabolism ; Membrane Proteins - metabolism ; Mice ; Nuclear Envelope - metabolism ; Receptors, Cytoplasmic and Nuclear</subject><ispartof>Human molecular genetics, 2023-02, Vol.32 (5), p.745-763</ispartof><rights>The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2023</rights><rights>The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c320t-2f09b81a57cfbfb02ff88e6a8ec7d221475cb52f46314455cba5485937957dc43</citedby><cites>FETCH-LOGICAL-c320t-2f09b81a57cfbfb02ff88e6a8ec7d221475cb52f46314455cba5485937957dc43</cites><orcidid>0000-0002-9936-2284</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36124691$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Patil, Shalaka</creatorcontrib><creatorcontrib>Deshpande, Shruti</creatorcontrib><creatorcontrib>Sengupta, Kundan</creatorcontrib><title>Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Abstract
Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs and micronuclei, with chromosomes showing higher frequency of losses, being enriched within the micronucleus. Furthermore, doxycycline-induced conditional depletion of LBR significantly increased tumor volumes that form within the subcutaneous xenografts of mice. Of note, the tumor-derived primary cells recapitulated chromosomal losses and gains, revealing a novel role for LBR as a tumor suppressor. Co-immunoprecipitation of LBR uncovered an association of LBR with telomere-associated factors. Interestingly, qPCR array-based gene expression profiling showed a significant upregulation of telomere repeat-binding factor 1 (TRF1) upon LBR depletion. Remarkably, TRF1 knockdown in the background of LBR depletion maintains chromosomal stability, unraveling a novel mechanism involving LBR and TRF in the maintenance of chromosomal stability in colorectal cancer cells.
Graphical Abstract
Graphical Abstract</description><subject>Animals</subject><subject>Carcinogenesis</subject><subject>Chromosomal Instability</subject><subject>Humans</subject><subject>Lamin B Receptor</subject><subject>Lamin Type B - metabolism</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Nuclear Envelope - metabolism</subject><subject>Receptors, Cytoplasmic and Nuclear</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1r3DAQhkVoyG7SnnIvOpVAcKIvy_KxDfmCkFzas5Hl0a6LZLmSHMi_r4K3PebyDsM8vAwPQueUXFHS8uu9310PgzaM10doS4UkFSOKf0Jb0kpRyZbIDTpN6TchVArenKANl5QJ2dItcs-LcaAjhukVXJgBzzFkGCfstC_5A0cwMOcQ14PJCec94B1MwQO2MXhs9iVDCl47PE4p6350Y37DehpwXnyIY6EhjekzOrbaJfhymGfo193tz5uH6unl_vHm-1NlOCO5Ypa0vaK6boztbU-YtUqB1ApMMzBGRVObvmZWSE6FqMuia6Hqljdt3QxG8DN0sfaWl_8skHLnx2TAOT1BWFLHGiqJUq1iBb1cURNDShFsN8fR6_jWUdK96-2K3u6gt9BfD8VL72H4z_7zWYBvKxCW-cOmv-qHhfg</recordid><startdate>20230219</startdate><enddate>20230219</enddate><creator>Patil, Shalaka</creator><creator>Deshpande, Shruti</creator><creator>Sengupta, Kundan</creator><general>Oxford University Press</general><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><orcidid>https://orcid.org/0000-0002-9936-2284</orcidid></search><sort><creationdate>20230219</creationdate><title>Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis</title><author>Patil, Shalaka ; Deshpande, Shruti ; Sengupta, Kundan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c320t-2f09b81a57cfbfb02ff88e6a8ec7d221475cb52f46314455cba5485937957dc43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Carcinogenesis</topic><topic>Chromosomal Instability</topic><topic>Humans</topic><topic>Lamin B Receptor</topic><topic>Lamin Type B - metabolism</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Nuclear Envelope - metabolism</topic><topic>Receptors, Cytoplasmic and Nuclear</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patil, Shalaka</creatorcontrib><creatorcontrib>Deshpande, Shruti</creatorcontrib><creatorcontrib>Sengupta, Kundan</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><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patil, Shalaka</au><au>Deshpande, Shruti</au><au>Sengupta, Kundan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2023-02-19</date><risdate>2023</risdate><volume>32</volume><issue>5</issue><spage>745</spage><epage>763</epage><pages>745-763</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Abstract
Lamin B Receptor (LBR) is an inner nuclear membrane protein that assembles the nuclear envelope post mitosis. Here we show that LBR depletion induces mitotic defects accompanied by recurrent chromosomal losses. In addition, LBR knockdown results in nuclear aberrations such as nuclear blebs and micronuclei, with chromosomes showing higher frequency of losses, being enriched within the micronucleus. Furthermore, doxycycline-induced conditional depletion of LBR significantly increased tumor volumes that form within the subcutaneous xenografts of mice. Of note, the tumor-derived primary cells recapitulated chromosomal losses and gains, revealing a novel role for LBR as a tumor suppressor. Co-immunoprecipitation of LBR uncovered an association of LBR with telomere-associated factors. Interestingly, qPCR array-based gene expression profiling showed a significant upregulation of telomere repeat-binding factor 1 (TRF1) upon LBR depletion. Remarkably, TRF1 knockdown in the background of LBR depletion maintains chromosomal stability, unraveling a novel mechanism involving LBR and TRF in the maintenance of chromosomal stability in colorectal cancer cells.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>36124691</pmid><doi>10.1093/hmg/ddac235</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-9936-2284</orcidid></addata></record> |
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| ispartof | Human molecular genetics, 2023-02, Vol.32 (5), p.745-763 |
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| language | eng |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Carcinogenesis Chromosomal Instability Humans Lamin B Receptor Lamin Type B - metabolism Membrane Proteins - metabolism Mice Nuclear Envelope - metabolism Receptors, Cytoplasmic and Nuclear |
| title | Nuclear envelope protein lamin B receptor protects the genome from chromosomal instability and tumorigenesis |
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