Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• DNA damage response (DDR) drugs are crucial in cancer therapy, but drug resistance is a significant clinical hurdle.
• Aberrant protein expression can drive therapeutic resistance in various cancers.

Purpose of the Study:

• To investigate the role of SYCP2, a meiotic protein, in cancer and its association with resistance to DDR drugs.
• To elucidate the mechanism by which SYCP2 influences DNA repair and drug sensitivity.

Main Methods:

• Analysis of SYCP2 expression in breast and ovarian cancer patient cohorts.
• Investigating SYCP2's role in DNA double-strand break (DSB) repair pathways, including transcription-coupled homologous recombination (TC-HR).
• Assessing the impact of SYCP2 on RAD51 recruitment and R-loop formation at DSBs.
• Evaluating the sensitivity of tumors with varying SYCP2 levels to PARP inhibitors, topoisomerase I (TOP1) inhibitors, and platinum-based chemotherapy.

Main Results:

• SYCP2 is aberrantly expressed in breast and ovarian cancers and linked to broad resistance to DDR drugs.
• SYCP2 enhances DSB repair via transcription-coupled homologous recombination (TC-HR) by promoting R-loop formation and RAD51 recruitment, independent of BRCA1.
• SYCP2 loss sensitizes tumors to PARP and TOP1 inhibitors.
• Clinical data show SYCP2 overexpression correlates with resistance to TOP1 inhibitors in breast cancer and platinum treatment in ovarian cancer.

Conclusions:

• SYCP2 promotes cancer cell resistance to DNA-damaging agents by enhancing R-loop-mediated DSB repair.
• Targeting SYCP2 presents a potential strategy to overcome DDR drug resistance in cancer therapy.