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

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.