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The SMC5/SMC6 complex is critical for resolving R-loop-induced transcription-replication conflicts.

Tong Wu1, Youhang Li1,2,3, Yuqin Zhao1

  • 1Department of Molecular and Cell Biology, The Scripps Research Institute, La Jolla, CA 92037,United States.

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|January 14, 2026
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Summary
This summary is machine-generated.

The SMC5/6 complex resolves transcription-replication conflicts (TRCs) that threaten genome stability. This discovery reveals a new pathway for treating tumors lacking senataxin (SETX).

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Area of Science:

  • Molecular Biology
  • Genetics
  • Genomics

Background:

  • R-loops are crucial for cell function but can destabilize genomes by causing transcription-replication conflicts (TRCs).
  • Senataxin (SETX) is an RNA/DNA helicase that resolves R-loops during replication.

Purpose of the Study:

  • To investigate the role of the SMC5/6 complex in resolving TRCs and maintaining genome stability.
  • To identify the molecular mechanisms by which SMC5/6 functions in TRC resolution.

Main Methods:

  • Investigated the synthetic lethal interaction between SMC5/6 and SETX.
  • Utilized cell-based assays to track recruitment of protein complexes to TRCs.
  • Analyzed the functional consequences of TRC resolution pathways.

Main Results:

  • The SMC5/6 complex is recruited to TRCs in senataxin-deficient cells, sensing DNA supercoiling.
  • SMC5/6 facilitates the recruitment of the BLM/TOP3A/RMI1/RMI2 (BTRR) complex to resolve TRCs.
  • The SMC5/6-BTRR axis, along with FANCM and FANCD2, mitigates TRC-induced genome instability.

Conclusions:

  • The SMC5/6 complex plays a critical role in sensing and resolving TRCs.
  • A novel SMC5/6-BTRR-FANCM-FANCD2 pathway is defined for mitigating genome instability.
  • Targeting this axis offers therapeutic potential for SETX-deficient tumors.