R-loop processing via REXO4-RNaseH1-mediated endo- and exo-cleavage coupling mode prevents genome instability and...

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• R-loop metabolism is linked to genome stability and tumor development.
• Understanding R-loop regulation is crucial for cancer research.

Purpose of the Study:

• To identify novel factors involved in R-loop degradation.
• To elucidate the mechanism of R-loop processing and its role in cancer.

Main Methods:

• Identification and characterization of exonuclease REXO4.
• Analysis of REXO4's collaboration with RNaseH1.
• Genome-wide R-loop profiling.
• Tumor mutation analysis.
• Drug sensitivity assays.

Main Results:

• REXO4 collaborates with RNaseH1 in an "endo/exo-cleavage coupling" manner to degrade R-loops.
• REXO4 degrades the RNA strand and stimulates RNaseH1 activity.
• REXO4 deficiency leads to increased R-loop burden and mutations in tumors.
• A novel inhibitor (REXO4-IN-17) of REXO4 was identified.
• Inhibition of REXO4 enhances sensitivity to chemotherapy and activates antitumor immunity.

Conclusions:

• A novel R-loop processing model involving "endo/exo-cleavage coupling" is proposed.
• REXO4 plays a critical role in maintaining genome stability by regulating R-loops.
• Targeting REXO4 presents a potential therapeutic strategy for cancer treatment and immunotherapy.