Sequential role of RAD51 paralog complexes in replication fork remodeling and restart

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Homologous recombination (HR) factors are involved in DNA replication fork remodeling and protection.
• HR-mediated fork remodeling contributes to cancer chemoresistance through unclear mechanisms.
• Five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) are recognized as critical tumor suppressors.

Purpose of the Study:

• To systematically investigate the role of RAD51 paralogs in DNA replication.
• To identify RAD51 paralog modulators during replication stress.
• To elucidate the distinct functions of RAD51 paralog subcomplexes in replication fork dynamics.

Main Methods:

• Screening for RAD51 paralog modulators upon replication stress.
• Single-molecule analysis of replication fork progression and architecture.
• Utilizing isogenic cellular systems, including BRCA2-defective cells.

Main Results:

• The RAD51 paralog BCDX2 subcomplex restrains replication fork progression and promotes fork reversal under stress.
• BCDX2 initiates degradation of reversed forks in BRCA2-defective cells, increasing genomic instability.
• The CX3 subcomplex is not essential for fork reversal but facilitates the restart of reversed forks.

Conclusions:

• RAD51 paralogs function sequentially to remodel and restart replication forks.
• The BCDX2 and CX3 subcomplexes have distinct roles in managing replication stress.
• Understanding these roles offers insights into cancer chemoresistance and genomic instability.