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RAD51C-XRCC3 complex regulates FANCM-mediated R-loop resolution to safeguard genome integrity.

Satyaranjan Sahoo1, Tarun Nagraj1, Debanjali Bhattacharya1

  • 1Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India.

Science Advances
|February 20, 2026
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Summary
This summary is machine-generated.

The RAD51C-XRCC3 complex prevents genome instability by resolving R-loops, a DNA structure implicated in Fanconi anemia (FA). This complex interacts with FANCM to manage R-loops during replication stress.

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Area of Science:

  • Molecular Biology
  • Genetics
  • DNA Repair

Background:

  • Fanconi anemia (FA) is a rare genetic disorder causing bone marrow failure, birth defects, and cancer susceptibility.
  • Mutations in RAD51 paralogs are linked to FA-like conditions and cancers, with known roles in DNA repair but unclear functions during replication stress.

Purpose of the Study:

  • To investigate the role of RAD51 paralogs, specifically the RAD51C-XRCC3 (CX3) complex, in Fanconi anemia pathway and replication stress response.
  • To elucidate the mechanism by which the CX3 complex influences R-loop processing and genome stability.

Main Methods:

  • Investigated the interaction between the CX3 complex and FANCM.
  • Assessed the impact of CX3 complex function and a pathological mutant (RAD51C R258H) on R-loop resolution and genome instability.
  • Examined the role of CX3 complex in transcription-replication collisions (TRCs).

Main Results:

  • The CX3 complex suppresses R-loops, TRCs, and genome instability under physiological and replication stress.
  • CX3 complex physically interacts with FANCM, promoting its recruitment to R-loop sites for resolution.
  • A pathological RAD51C mutant impairs FANCM interaction and R-loop processing, leading to genome instability.

Conclusions:

  • The CX3 complex plays a crucial role in the Fanconi anemia pathway by mediating R-loop tolerance.
  • CX3 complex prevents R-loop-induced genome instability through FANCM-dependent R-loop resolution, independent of its fork maintenance role.