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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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MT1-MMP-dependent ECM processing regulates laminB1 stability and mediates replication fork restart.

Varsha Thakur1, Juliano Tiburcio de Freitas1, Yuan Li1

  • 1Department of Dermatology, University of Miami Miller School of Medicine, Miami, FL, United States of America.

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Matrix metalloproteinase MT1-MMP promotes cancer cell resistance to radiotherapy. Its inhibition stabilizes laminB1, preventing DNA damage and replication fork collapse in breast cancer.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Radiotherapy is a primary cancer treatment.
  • Membrane-bound matrix metalloproteinase MT1-MMP confers radio- and chemotherapy resistance in breast cancer.
  • MT1-MMP acts via extracellular matrix processing and integrinβ1/FAK signaling.

Purpose of the Study:

  • To investigate the role of laminB1 in MT1-MMP-mediated radioresistance.
  • To elucidate the mechanism by which MT1-MMP influences DNA repair and replication fork stability.

Main Methods:

  • Investigated the interaction between FAK and laminB1.
  • Assessed the localization of laminB1 at replication forks.
  • Examined the effect of MT1-MMP inhibition on laminB1 expression and DNA damage.
  • Restored laminB1 expression to evaluate its impact on replication fork stability.

Main Results:

  • FAK interacts with laminB1, enhancing its stability.
  • Stable laminB1 is localized at replication forks, aiding in the positioning of protection factors.
  • MT1-MMP inhibition leads to laminB1 downregulation, causing replication fork stalling and collapse.
  • Restoration of laminB1 expression rescues replication fork stability and reduces DNA damage.

Conclusions:

  • LaminB1 stability and replication fork restart are regulated by MT1-MMP-dependent extracellular matrix remodeling.
  • This pathway represents a novel mechanism contributing to radioresistance in breast cancer.
  • Targeting MT1-MMP or modulating laminB1 could be potential therapeutic strategies for overcoming treatment resistance.