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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Autores principales:	Varsha Thakur, Juliano Tiburcio de Freitas, Yuan Li, Keman Zhang, Alyssa Savadelis, Barbara Bedogni
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8877003f627d46f59386fd6690d3d1d4
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spelling	oai:doaj.org-article:8877003f627d46f59386fd6690d3d1d42021-12-02T20:05:10ZMT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.1932-620310.1371/journal.pone.0253062https://doaj.org/article/8877003f627d46f59386fd6690d3d1d42021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253062https://doaj.org/toc/1932-6203Radiotherapy 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.Varsha ThakurJuliano Tiburcio de FreitasYuan LiKeman ZhangAlyssa SavadelisBarbara BedogniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0253062 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Varsha Thakur Juliano Tiburcio de Freitas Yuan Li Keman Zhang Alyssa Savadelis Barbara Bedogni MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.
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.
format	article
author	Varsha Thakur Juliano Tiburcio de Freitas Yuan Li Keman Zhang Alyssa Savadelis Barbara Bedogni
author_facet	Varsha Thakur Juliano Tiburcio de Freitas Yuan Li Keman Zhang Alyssa Savadelis Barbara Bedogni
author_sort	Varsha Thakur
title	MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.
title_short	MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.
title_full	MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.
title_fullStr	MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.
title_full_unstemmed	MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.
title_sort	mt1-mmp-dependent ecm processing regulates laminb1 stability and mediates replication fork restart.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/8877003f627d46f59386fd6690d3d1d4
work_keys_str_mv	AT varshathakur mt1mmpdependentecmprocessingregulateslaminb1stabilityandmediatesreplicationforkrestart AT julianotiburciodefreitas mt1mmpdependentecmprocessingregulateslaminb1stabilityandmediatesreplicationforkrestart AT yuanli mt1mmpdependentecmprocessingregulateslaminb1stabilityandmediatesreplicationforkrestart AT kemanzhang mt1mmpdependentecmprocessingregulateslaminb1stabilityandmediatesreplicationforkrestart AT alyssasavadelis mt1mmpdependentecmprocessingregulateslaminb1stabilityandmediatesreplicationforkrestart AT barbarabedogni mt1mmpdependentecmprocessingregulateslaminb1stabilityandmediatesreplicationforkrestart
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MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.

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