Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Ubiquitylation is essential for cellular DNA double-strand break (DSB) repair.
• Unrepaired DSBs lead to genomic instability and diseases like cancer and neurodegeneration.

Purpose of the Study:

• To systematically profile human ubiquitin E2 enzymes for their roles in cellular DSB responses.
• To identify novel components involved in ubiquitylation cascades downstream of E2 enzymes in DSB repair.

Main Methods:

• Comprehensive, multilayered screening of human ubiquitin E2 enzymes.
• Utilizing the UBE2D family as an exemplary E2 group to identify downstream factors.
• Investigating the function of identified factors in cellular DSB repair pathways.

Main Results:

• Identified the nuclear E3 ligase RNF138 as a critical factor promoting homologous recombination (HR).
• Demonstrated that UBE2Ds and RNF138 collaborate to promote CtIP ubiquitylation and accrual at DNA damage sites.
• Showed that UBE2Ds and RNF138 act at early resection stages of DSB repair.

Conclusions:

• RNF138 and UBE2Ds are key regulators of DNA double-strand break repair via homologous recombination.
• This study provides mechanistic insights into DSB repair regulation.
• The findings offer a valuable resource for future research on E2 enzymes and DSB repair.