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

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.

MMP-1 and ADAM10 as Targets for Therapeutic Intervention in Idiopathic Pulmonary Fibrosis

“…Notwithstanding the smallness of the effect in the production of MMP-14 in IPF lungs, we note that MMP-14 (also known as membrane type1 (MT1)-MMP) has been shown recently to mediate DNA damage repair. 18 Furthermore, our results of decreased MMP-14 levels in human IPF lungs are in agreement with a recent study in which MMP-14 deficiency exacerbated fibrosis in bleomycin-induced IPF. 19 The proof of whether MMP-8 and/or MMP-14 perform mitigation functions in IPF�a "yin-yang" cellular struggle against the detrimental enzyme(s)�should await future studies.…”

“…In an earlier study, we have shown that MMP-8 facilitates healing in diabetic wounds, and one wonders if a similar role might apply in IPF lungs. , With diminution of MMP-8 in the diseased tissue being as much as 70-fold, if indeed this enzyme would engage in repair mechanisms of damage in IPF, the repair function would be undermined. Notwithstanding the smallness of the effect in the production of MMP-14 in IPF lungs, we note that MMP-14 (also known as membrane type1 (MT1)-MMP) has been shown recently to mediate DNA damage repair . Furthermore, our results of decreased MMP-14 levels in human IPF lungs are in agreement with a recent study in which MMP-14 deficiency exacerbated fibrosis in bleomycin-induced IPF .…”

Mechanism and role of nuclear laminin B1 in cell senescence and malignant tumors

“…MT1-MMP is involved in extracellular matrix and basement membrane remodeling, thus enabling stability of LMNB1. MT1-MMP also promotes radiological and chemical resistance by destroying the extracellular matrix, which subsequently promotes restart of the replication fork [ 95 ]. Other studies have shown that chronic strain and stress can decrease LMNB1 expression levels and eventually led to DNA damage and nuclear membrane disruption; moreover, the release of cytoplasmic DNA activated the cGAS-STING signaling pathway that is dependent on cytoplasmic DNA response gene programs.…”

“…MT1-MMP is involved in extracellular matrix and basement membrane remodeling, thus enabling stability of LMNB1. MT1-MMP also promotes radiological and chemical resistance by destroying the extracellular matrix, which subsequently promotes restart of the replication fork [95].…”