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

Yumin Wang1, Boya Gao1,2, Luyuan Zhang3

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, 13th Street, Charlestown, MA, 02129, USA.

Nature Communications
|February 21, 2024
PubMed

Insights

A meiotic protein, SYCP2, is overexpressed in breast and ovarian cancers, driving resistance to DNA damage response (DDR) drugs by enhancing DNA repair. Targeting SYCP2 may improve cancer therapy outcomes.

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.

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