MePCE promotes homologous recombination through coordinating R-loop resolution at DNA double-stranded breaks

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• MePCE protein regulates transcription elongation factor P-TEFb partitioning.
• Its role in chromatin function, particularly DNA repair, is not well understood.
• The 7SK ribonuclear protein complex (RNPc) involves MePCE and LARP7.

Purpose of the Study:

• To investigate the function of MePCE on chromatin, specifically in DNA double-stranded break (DSB) repair.
• To elucidate the interaction of MePCE with R-loop processing and DNA repair factors.
• To understand the role of MePCE in the context of 7SK RNPc dynamics at DSBs.

Main Methods:

• Investigated MePCE recruitment to DSBs.
• Assessed the impact of MePCE depletion on homologous recombination (HR) repair.
• Analyzed RAD51 loading and R-loop levels at DSBs.
• Examined interactions with R-loop processing factors and LARP7.

Main Results:

• MePCE is recruited to DSBs and interacts with DNA repair factors.
• MePCE depletion impairs HR, reduces RAD51 loading, and increases R-loop levels at DSBs.
• MePCE depletion alters LARP7 interaction with R-loops, leading to its degradation by BRCA1/BARD1.
• Dynamic regulation of 7SK RNPc at DSBs was uncovered.

Conclusions:

• MePCE plays a crucial role in DSB repair by homologous recombination.
• MePCE's function at DSBs involves R-loop processing and interaction with BRCA1/BARD1 pathway.
• These findings explain the synthetic lethality observed between MePCE and BRCA1 deficiency.