PRL-3 promotes telomere deprotection and chromosomal instability
Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL...
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| Veröffentlicht in: | Nucleic acids research 2017-06, Vol.45 (11), p.6546-6571 |
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| creator | Lian, Shenyi Meng, Lin Yang, Yongyong Ma, Ting Xing, Xiaofang Feng, Qin Song, Qian Liu, Caiyun Tian, Zhihua Qu, Like Shou, Chengchao |
| description | Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence. Furthermore, PRL-3 dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. PRL-3-promoted telomere deprotection, DNA damage response and senescence are counteracted by disruption of PRL-3-RAP1 complex or expression of ectopic TRF2. Examination of clinical samples showed that PRL-3 status positively correlates with telomere deprotection and senescence. PRL-3 transgenic mice exhibit hallmarks of telomere deprotection and senescence and are susceptible to dextran sodium sulfate-induced colon malignancy. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis. |
| doi_str_mv | 10.1093/nar/gkx392 |
| format | Article |
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We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence. Furthermore, PRL-3 dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. PRL-3-promoted telomere deprotection, DNA damage response and senescence are counteracted by disruption of PRL-3-RAP1 complex or expression of ectopic TRF2. Examination of clinical samples showed that PRL-3 status positively correlates with telomere deprotection and senescence. PRL-3 transgenic mice exhibit hallmarks of telomere deprotection and senescence and are susceptible to dextran sodium sulfate-induced colon malignancy. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkx392</identifier><identifier>PMID: 28482095</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Carcinogenesis - genetics ; Cell Line, Tumor ; Cellular Senescence ; Chlorocebus aethiops ; Chromosomal Instability ; Colonic Neoplasms - chemically induced ; Colonic Neoplasms - genetics ; COS Cells ; DNA Damage ; Genome Integrity, Repair and ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Proteins - physiology ; Protein Tyrosine Phosphatases - physiology ; Telomere Homeostasis ; Telomere-Binding Proteins - metabolism ; Telomeric Repeat Binding Protein 2 - metabolism</subject><ispartof>Nucleic acids research, 2017-06, Vol.45 (11), p.6546-6571</ispartof><rights>The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-39a4686c3dfe81138e5aaeef46e367c097351ff7de6eda8139ef13d51878c5233</citedby><cites>FETCH-LOGICAL-c378t-39a4686c3dfe81138e5aaeef46e367c097351ff7de6eda8139ef13d51878c5233</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/PMC5499835/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499835/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28482095$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lian, Shenyi</creatorcontrib><creatorcontrib>Meng, Lin</creatorcontrib><creatorcontrib>Yang, Yongyong</creatorcontrib><creatorcontrib>Ma, Ting</creatorcontrib><creatorcontrib>Xing, Xiaofang</creatorcontrib><creatorcontrib>Feng, Qin</creatorcontrib><creatorcontrib>Song, Qian</creatorcontrib><creatorcontrib>Liu, Caiyun</creatorcontrib><creatorcontrib>Tian, Zhihua</creatorcontrib><creatorcontrib>Qu, Like</creatorcontrib><creatorcontrib>Shou, Chengchao</creatorcontrib><title>PRL-3 promotes telomere deprotection and chromosomal instability</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence. Furthermore, PRL-3 dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. PRL-3-promoted telomere deprotection, DNA damage response and senescence are counteracted by disruption of PRL-3-RAP1 complex or expression of ectopic TRF2. Examination of clinical samples showed that PRL-3 status positively correlates with telomere deprotection and senescence. PRL-3 transgenic mice exhibit hallmarks of telomere deprotection and senescence and are susceptible to dextran sodium sulfate-induced colon malignancy. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.</description><subject>Animals</subject><subject>Carcinogenesis - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cellular Senescence</subject><subject>Chlorocebus aethiops</subject><subject>Chromosomal Instability</subject><subject>Colonic Neoplasms - chemically induced</subject><subject>Colonic Neoplasms - genetics</subject><subject>COS Cells</subject><subject>DNA Damage</subject><subject>Genome Integrity, Repair and</subject><subject>Humans</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Neoplasm Proteins - physiology</subject><subject>Protein Tyrosine Phosphatases - physiology</subject><subject>Telomere Homeostasis</subject><subject>Telomere-Binding Proteins - metabolism</subject><subject>Telomeric Repeat Binding Protein 2 - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkF1LwzAUhoMoOqc3_gDppQh1SU-TJjeiDL9goIhehyw93aptM5NM3L-3Y1P06sB7Ht5zeAg5YfSCUQWjzvjR7P0LVLZDBgxEluZKZLtkQIHylNFcHpDDEN4oZTnj-T45yGQuM6r4gFw9PU9SSBbetS5iSCI2rkWPSYl9FtHG2nWJ6crEztdMcK1pkroL0Uzrpo6rI7JXmSbg8XYOyevtzcv4Pp083j2MryephULGFJTJhRQWygolYyCRG4NY5QJBFJaqAjirqqJEgaWRDBRWDErOZCEtzwCG5HLTu1hOWywtdtGbRi983Rq_0s7U-v-mq-d65j41z5WSwPuCs22Bdx9LDFG3dbDYNKZDtwyaSSWkYoyLHj3foNa7EDxWv2cY1WvluleuN8p7-PTvY7_oj2P4BkVmf0E</recordid><startdate>20170620</startdate><enddate>20170620</enddate><creator>Lian, Shenyi</creator><creator>Meng, Lin</creator><creator>Yang, Yongyong</creator><creator>Ma, Ting</creator><creator>Xing, Xiaofang</creator><creator>Feng, Qin</creator><creator>Song, Qian</creator><creator>Liu, Caiyun</creator><creator>Tian, Zhihua</creator><creator>Qu, Like</creator><creator>Shou, Chengchao</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><scope>5PM</scope></search><sort><creationdate>20170620</creationdate><title>PRL-3 promotes telomere deprotection and chromosomal instability</title><author>Lian, Shenyi ; Meng, Lin ; Yang, Yongyong ; Ma, Ting ; Xing, Xiaofang ; Feng, Qin ; Song, Qian ; Liu, Caiyun ; Tian, Zhihua ; Qu, Like ; Shou, Chengchao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-39a4686c3dfe81138e5aaeef46e367c097351ff7de6eda8139ef13d51878c5233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Carcinogenesis - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cellular Senescence</topic><topic>Chlorocebus aethiops</topic><topic>Chromosomal Instability</topic><topic>Colonic Neoplasms - chemically induced</topic><topic>Colonic Neoplasms - genetics</topic><topic>COS Cells</topic><topic>DNA Damage</topic><topic>Genome Integrity, Repair and</topic><topic>Humans</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Neoplasm Proteins - physiology</topic><topic>Protein Tyrosine Phosphatases - physiology</topic><topic>Telomere Homeostasis</topic><topic>Telomere-Binding Proteins - metabolism</topic><topic>Telomeric Repeat Binding Protein 2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lian, Shenyi</creatorcontrib><creatorcontrib>Meng, Lin</creatorcontrib><creatorcontrib>Yang, Yongyong</creatorcontrib><creatorcontrib>Ma, Ting</creatorcontrib><creatorcontrib>Xing, Xiaofang</creatorcontrib><creatorcontrib>Feng, Qin</creatorcontrib><creatorcontrib>Song, Qian</creatorcontrib><creatorcontrib>Liu, Caiyun</creatorcontrib><creatorcontrib>Tian, Zhihua</creatorcontrib><creatorcontrib>Qu, Like</creatorcontrib><creatorcontrib>Shou, Chengchao</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>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lian, Shenyi</au><au>Meng, Lin</au><au>Yang, Yongyong</au><au>Ma, Ting</au><au>Xing, Xiaofang</au><au>Feng, Qin</au><au>Song, Qian</au><au>Liu, Caiyun</au><au>Tian, Zhihua</au><au>Qu, Like</au><au>Shou, Chengchao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PRL-3 promotes telomere deprotection and chromosomal instability</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2017-06-20</date><risdate>2017</risdate><volume>45</volume><issue>11</issue><spage>6546</spage><epage>6571</epage><pages>6546-6571</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence. Furthermore, PRL-3 dissociates RAP1 and TRF2 from telomeric DNA in vitro and in cells. PRL-3-promoted telomere deprotection, DNA damage response and senescence are counteracted by disruption of PRL-3-RAP1 complex or expression of ectopic TRF2. Examination of clinical samples showed that PRL-3 status positively correlates with telomere deprotection and senescence. PRL-3 transgenic mice exhibit hallmarks of telomere deprotection and senescence and are susceptible to dextran sodium sulfate-induced colon malignancy. Our results uncover a novel role of PRL-3 in tumor development through its adverse impact on telomere homeostasis.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>28482095</pmid><doi>10.1093/nar/gkx392</doi><tpages>26</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carcinogenesis - genetics Cell Line, Tumor Cellular Senescence Chlorocebus aethiops Chromosomal Instability Colonic Neoplasms - chemically induced Colonic Neoplasms - genetics COS Cells DNA Damage Genome Integrity, Repair and Humans Mice, Inbred C57BL Mice, Transgenic Neoplasm Proteins - physiology Protein Tyrosine Phosphatases - physiology Telomere Homeostasis Telomere-Binding Proteins - metabolism Telomeric Repeat Binding Protein 2 - metabolism |
| title | PRL-3 promotes telomere deprotection and chromosomal instability |
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