Low-molecular-weight cyclin E (LMW-E) overexpression promotes genomic instability in human mammary epithelial cells and associates with genomic instability in early-stage breast tumors. Full-length cyclin E (FL-cycE) overexpression leads to accumulation of replication stress, DNA damage, and ultimately cell death. Mechanistically, LMW-E upregulates the expression of CDC6, RAD51, and C17orf53. LMW-E, but not FL-cycE, facilitates replication stress tolerance by promoting pre-replication complex assembly in a CDC6 dependent manner and DNA damage repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with small molecule inhibitors significantly decreased LMW-E–overexpressing cell viability. In breast tumor samples, positive LMW-E status independently predicts genomic instability and tumor recurrence.
- Mi Li
- Spiridon Tsavachidis
- Khandan Keyomarsi
