TIPIN is essential for chromosome stability and cell viability in BRCA1-deficient cells

The mutations of breast cancer type 1 susceptibility gene (BRCA1) cause hereditary breast cancer. One of the medical revolutions of cancer therapy for BRCA1-mutated breast cancer is the drug approval of Poly (ADP-ribose) polymerase (PARP) inhibitors because of the synthetic lethal interaction between BRCA1 mutation and PARP inhibition. Here, we report another synthetic lethal interaction between BRCA1 and TIMELESS interacting protein (TIPIN), the latter of which encodes a protein involved in DNA replication, DNA damage checkpoint and sister chromatid cohesion. Cells deficient for both BRCA1 and TIPIN die due to elevated chromosomal aberrations including chromosomal breaks and radial chromosomes. The synthetic lethality of TIPIN/BRCA1-deficient cells is restored by the depletion of Tumor protein p53 binding protein 1 (53BP1), which prevents homologous recombination (HR) by its restricting DNA processing. Thus, spontaneous DNA lesions in TIPIN deficient cells could be preferentially repaired by BRCA1-mediated HR pathway. The viability of TIPIN/53BP1/BRCA1 triple mutant is lost by the depletion of Ring finger protein 8 (RNF8) E3-ubiquitin ligase, implicating that RNF8-mediated sub-HR pathway may work in a complementary manner of BRCA1 and 53BP1 pathway.