MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart
Radiotherapy remains a mainstay of treatment for a majority of cancer patients. We have previously shown that the membrane bound matrix metalloproteinase MT1-MMP confers radio- and chemotherapy resistance to breast cancer via processing of the ECM and activation of integrinβ1/FAK signaling. Here, we...
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description | Radiotherapy remains a mainstay of treatment for a majority of cancer patients. We have previously shown that the membrane bound matrix metalloproteinase MT1-MMP confers radio- and chemotherapy resistance to breast cancer via processing of the ECM and activation of integrinβ1/FAK signaling. Here, we further discovered that the nuclear envelope protein laminB1 is a potential target of integrinβ1/FAK. FAK interacts with laminB1 contributing to its stability. Stable laminB1 is found at replication forks (RFs) where it is likely to allow the proper positioning of RF protection factors, thus preventing RF degradation. Indeed, restoration of laminB1 expression rescues replication fork stalling and collapse that occurs upon MT1-MMP inhibition, and reduces DNA damage in breast cancer cells. Together, these data highlight a novel mechanism of laminB1 stability and replication fork restart via MT1-MMP dependent extracelluar matrix remodeling. |
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We have previously shown that the membrane bound matrix metalloproteinase MT1-MMP confers radio- and chemotherapy resistance to breast cancer via processing of the ECM and activation of integrinβ1/FAK signaling. Here, we further discovered that the nuclear envelope protein laminB1 is a potential target of integrinβ1/FAK. FAK interacts with laminB1 contributing to its stability. Stable laminB1 is found at replication forks (RFs) where it is likely to allow the proper positioning of RF protection factors, thus preventing RF degradation. Indeed, restoration of laminB1 expression rescues replication fork stalling and collapse that occurs upon MT1-MMP inhibition, and reduces DNA damage in breast cancer cells. Together, these data highlight a novel mechanism of laminB1 stability and replication fork restart via MT1-MMP dependent extracelluar matrix remodeling.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0253062</identifier><identifier>PMID: 34237080</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Antibodies ; Biochemistry ; Biology and life sciences ; Biotechnology ; Blotting, Western ; Breast cancer ; Cancer therapies ; Cell cycle ; Cell Line ; Chemoresistance ; Chemotherapy ; Comet Assay ; Complications and side effects ; Composition ; Deoxyribonucleic acid ; Dermatology ; DNA ; DNA damage ; DNA Repair ; DNA Replication ; Drug dosages ; Extracellular matrix ; Extracellular Matrix - enzymology ; Extracellular Matrix - metabolism ; Fluorescent Antibody Technique ; Focal adhesion kinase ; Humans ; Immunoprecipitation ; Lamin Type B - metabolism ; Matrix metalloproteinase ; Matrix Metalloproteinase 14 - metabolism ; Matrix metalloproteinases ; Medicine ; Medicine and Health Sciences ; Metalloproteinase ; Patient outcomes ; Radiation therapy ; Radiotherapy ; Real-Time Polymerase Chain Reaction ; Replication ; Replication forks ; Research and Analysis Methods ; Stability ; Stalling ; Viral envelope proteins</subject><ispartof>PloS one, 2021-07, Vol.16 (7), p.e0253062</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Thakur 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>2021 Thakur et al 2021 Thakur et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-401a8ce0665e43138cccfaca36514c49a4735fd2bc87c55117c076fbff7cb0313</citedby><cites>FETCH-LOGICAL-c692t-401a8ce0665e43138cccfaca36514c49a4735fd2bc87c55117c076fbff7cb0313</cites><orcidid>0000-0002-5180-2164 ; 0000-0002-1539-9064 ; 0000-0002-8556-2939</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/PMC8266045/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266045/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34237080$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Maiorano, Domenico</contributor><creatorcontrib>Thakur, Varsha</creatorcontrib><creatorcontrib>Tiburcio de Freitas, Juliano</creatorcontrib><creatorcontrib>Li, Yuan</creatorcontrib><creatorcontrib>Zhang, Keman</creatorcontrib><creatorcontrib>Savadelis, Alyssa</creatorcontrib><creatorcontrib>Bedogni, Barbara</creatorcontrib><title>MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Radiotherapy remains a mainstay of treatment for a majority of cancer patients. We have previously shown that the membrane bound matrix metalloproteinase MT1-MMP confers radio- and chemotherapy resistance to breast cancer via processing of the ECM and activation of integrinβ1/FAK signaling. Here, we further discovered that the nuclear envelope protein laminB1 is a potential target of integrinβ1/FAK. FAK interacts with laminB1 contributing to its stability. Stable laminB1 is found at replication forks (RFs) where it is likely to allow the proper positioning of RF protection factors, thus preventing RF degradation. Indeed, restoration of laminB1 expression rescues replication fork stalling and collapse that occurs upon MT1-MMP inhibition, and reduces DNA damage in breast cancer cells. Together, these data highlight a novel mechanism of laminB1 stability and replication fork restart via MT1-MMP dependent extracelluar matrix remodeling.</description><subject>Antibodies</subject><subject>Biochemistry</subject><subject>Biology and life sciences</subject><subject>Biotechnology</subject><subject>Blotting, Western</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell Line</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Comet Assay</subject><subject>Complications and side effects</subject><subject>Composition</subject><subject>Deoxyribonucleic acid</subject><subject>Dermatology</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Repair</subject><subject>DNA Replication</subject><subject>Drug dosages</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - enzymology</subject><subject>Extracellular Matrix - metabolism</subject><subject>Fluorescent Antibody Technique</subject><subject>Focal adhesion kinase</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Lamin Type B - 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We have previously shown that the membrane bound matrix metalloproteinase MT1-MMP confers radio- and chemotherapy resistance to breast cancer via processing of the ECM and activation of integrinβ1/FAK signaling. Here, we further discovered that the nuclear envelope protein laminB1 is a potential target of integrinβ1/FAK. FAK interacts with laminB1 contributing to its stability. Stable laminB1 is found at replication forks (RFs) where it is likely to allow the proper positioning of RF protection factors, thus preventing RF degradation. Indeed, restoration of laminB1 expression rescues replication fork stalling and collapse that occurs upon MT1-MMP inhibition, and reduces DNA damage in breast cancer cells. Together, these data highlight a novel mechanism of laminB1 stability and replication fork restart via MT1-MMP dependent extracelluar matrix remodeling.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>34237080</pmid><doi>10.1371/journal.pone.0253062</doi><tpages>e0253062</tpages><orcidid>https://orcid.org/0000-0002-5180-2164</orcidid><orcidid>https://orcid.org/0000-0002-1539-9064</orcidid><orcidid>https://orcid.org/0000-0002-8556-2939</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Antibodies Biochemistry Biology and life sciences Biotechnology Blotting, Western Breast cancer Cancer therapies Cell cycle Cell Line Chemoresistance Chemotherapy Comet Assay Complications and side effects Composition Deoxyribonucleic acid Dermatology DNA DNA damage DNA Repair DNA Replication Drug dosages Extracellular matrix Extracellular Matrix - enzymology Extracellular Matrix - metabolism Fluorescent Antibody Technique Focal adhesion kinase Humans Immunoprecipitation Lamin Type B - metabolism Matrix metalloproteinase Matrix Metalloproteinase 14 - metabolism Matrix metalloproteinases Medicine Medicine and Health Sciences Metalloproteinase Patient outcomes Radiation therapy Radiotherapy Real-Time Polymerase Chain Reaction Replication Replication forks Research and Analysis Methods Stability Stalling Viral envelope proteins |
title | MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart |
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