MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart

Varsha Thakur, Juliano Tiburcio de Freitas, Yuan Li, Keman Zhang, Alyssa Savadelis, Barbara Bedogni

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere0253062
JournalPloS one
Volume16
Issue number7 July
DOIs
StatePublished - Jul 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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