KCTD10 is a sensor for co-directional transcription-replication conflicts

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Transcription-replication conflicts (TRCs) are a significant source of genome instability in mammals.
• The mechanisms by which cells manage TRCs and facilitate replisome bypass remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms by which cells resolve TRCs and maintain genome stability.
• To identify the role of the CUL3-KCTD10 E3 ligase in managing conflicts between DNA replication and transcription.

Main Methods:

• Investigated the interaction of KCTD10 with both the replisome and transcription machinery.
• Analyzed the role of CUL3-KCTD10 in ubiquitination and removal of the RNA polymerase factor TCEA2.
• Assessed the impact of KCTD10 deficiency on TRC accumulation and DNA damage.

Main Results:

• CUL3-KCTD10 E3 ligase detects TRCs and promotes RNA polymerase remodeling for replisome bypass.
• KCTD10 acts as a bivalent adaptor, sensing co-directional TRCs and facilitating CUL3 recruitment.
• Absence of KCTD10 leads to increased TCEA2 retention, TRC accumulation, and DNA damage.

Conclusions:

• The CUL3-KCTD10 complex bridges transcription and replication machinery to resolve conflicts.
• This process is crucial for allowing DNA replication through transcriptionally active regions.
• Findings provide a framework for understanding how transcription-replication coordination maintains genome stability.