ABL1-mediated tyrosine phosphorylation of SYCP2 contributes to transcription-coupled homologous recombination and platinum resistance in ovarian cancer

Treatment of patients with platinum-resistant ovarian cancer is a major clinical challenge. We found that high expression of a meiotic protein, Synaptonemal Complex Protein 2 (SYCP2), is associated with platinum resistance and tyrosine kinase ABL1 inhibitor sensitivity in ovarian cancer. We demonstrate that tyrosine kinase ABL1 inhibitors inhibit cancer cell proliferation more efficiently in ovarian cancer cell lines with SYCP2 overexpression. Moreover, ABL1 inhibition effectively prevents tumor growth <i>in vivo</i>. Mechanistically, we identified a phosphorylation motif [RK]-x(2,3)-[DE]-x(2,3)-Y in SYCP2 and found that abolishing ABL1-mediated phosphorylation of SYCP2 at its tyrosine (Y) 739 within this motif renders ABL1 sensitivity of cancer cells. Importantly, ABL1 and SYCP2 colocalize at sites of R-loops after damage and promote transcription-coupled homologous recombination. Moreover, ABL1-mediated Y739 phosphorylation of SYCP2 promotes function of SYCP2 at sites of R-loops by facilitating RAD51 localization and repair, contributing to ovarian cancer cell survival. Overall, these findings highlight a novel therapeutic mechanism where ABL1 inhibitors induce cell death in platinum-resistant ovarian cancer by impairing transcription-coupled homologous recombination repair.