Interaction of NDRG1 and MRE11 Modulates DNA Replication and Repair.

Area of Science:

• Molecular biology
• Cancer research
• DNA damage and repair

Background:

• Pancreatic ductal adenocarcinoma (PDAC) exhibits limited treatment options and frequent chemoresistance.
• Cancer-associated fibroblasts (CAFs) contribute to PDAC chemoresistance via mechanisms like N-myc downstream regulated gene 1 (NDRG1) signaling.
• NDRG1, when phosphorylated by CAF-induced signaling, promotes DNA repair and protects PDAC cells from chemotherapy.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying NDRG1-mediated DNA repair and replication.
• To identify NDRG1 binding partners involved in chemoresistance.
• To investigate the role of identified partners in DNA repair and replication fork stability.

Main Methods:

• Utilized BioID proximity labeling to identify NDRG1 interacting proteins.
• Conducted DNA replication and repair assays, including Comet and DNA fiber assays.
• Assessed the functional impact of NDRG1 and identified partner interactions on DNA integrity under replication stress.

Main Results:

• Identified meiotic recombination 11 (MRE11), a DNA damage response nuclease, as a NDRG1 interacting protein.
• Observed NDRG1-MRE11 interaction enrichment during late S/early G2 phases and under replication stress, suggesting an indirect interaction.
• Demonstrated that blocking NDRG1 phosphorylation or MRE11 exonuclease activity protects nascent DNA at stalled replication forks; NDRG1 is required for MRE11 activity in this context.

Conclusions:

• Uncovered a novel protein complex between NDRG1 and MRE11.
• This NDRG1-MRE11 complex plays a critical role in processing stalled replication forks.
• The complex represents a potential therapeutic target for overcoming chemoresistance in PDAC.