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Interaction of NDRG1 and TGM2 Modulates DNA Replication and Repair

Hanna M Doh1,2,3, Nina Kozlova1,2,4, Kayla A Cruz1,2,3

  • 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Molecular Cancer Research : MCR
|March 31, 2026
PubMed

Insights

Cancer cells face DNA replication stress. This study reveals how NDRG1 and TGM2 proteins interact to stabilize DNA replication forks, aiding cancer cell survival under stress.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • Tumor cells experience DNA replication stress from internal and external factors.
  • The N-myc downstream regulated gene 1 (NDRG1) pathway is involved in mitigating this stress.
  • Extracellular matrix (ECM) signaling activates NDRG1 for protection against chemotherapy-induced replication stress.

Purpose of the Study:

  • To elucidate the mechanistic details of NDRG1's role in DNA replication.
  • To identify novel NDRG1 binding partners involved in DNA replication regulation.

Main Methods:

  • Protein-protein interaction studies to identify NDRG1 binding partners.
  • Cellular assays to assess replication fork progression upon TGM2 depletion.
  • Biochemical assays to investigate TGM2 catalytic activity and localization.

Main Results:

  • Transglutaminase 2 (TGM2) was identified as a novel NDRG1 binding partner.
  • The NDRG1-TGM2 interaction is enhanced by chemotherapy and ECM-induced signaling.
  • TGM2 depletion impairs replication fork progression, dependent on its catalytic activity and nuclear localization.
  • A specific binding site between NDRG1 and TGM2 was identified, crucial for DNA replication.

Conclusions:

  • NDRG1 and TGM2 have a previously unrecognized nuclear function in maintaining DNA replication fork stability.
  • This interaction represents a stress-responsive mechanism supporting replication homeostasis in cancer cells.
  • The findings advance understanding of how extracellular signals integrate with DNA replication and repair pathways in cancer.

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