Moonlighting role of meiotic SYCP1 in breast cancer: A chromatin-bound regulator of DNA repair, transcription, and drug resistance
- Louise C. Brennan
- Oleg V. Grinchuk
- Miguel Pachon-Penalba
- Ieng F. Sou
- Conor J. Fawcett
- Claudia G. Nogueira
- Megan Guthrie
- Andrew D. Bates
- Megan Hine
- Amanda Thomaz
- Andew B. Fielding
- Owen R. Davies
- Wee-Wei Tee
- Urszula L. McClurg
2026-07-08
Maintenance of genome integrity is essential for cellular homeostasis, and its perturbation leads to tumorigenesis. Here, we uncover an unanticipated somatic role for the synaptonemal complex protein SYCP1, previously regarded as strictly meiosis specific, in a broad spectrum of human cancers including breast cancer. Through integrative genomic, proteomic, and functional analyses, we demonstrate that SYCP1 is aberrantly reexpressed in tumor cells, where it actively promotes DNA damage repair, cell cycle progression, and malignant growth. SYCP1 binds chromatin at regulatory elements and directly controls transcriptional programs governing genome maintenance, including key effectors such as CCNB1 , PCNA , RAD51C , and H2AX . Loss of SYCP1 impairs DNA repair kinetics, attenuates tumor cell proliferation and migration, and increases sensitivity to chemotherapeutics cisplatin and gemcitabine. Mechanistically, SYCP1 coimmunoprecipitates with chromatin remodeling complexes and transcription factors SP1 and SP2 and modulates their genomic occupancy and oncogenic transcriptional outputs. Clinically, high SYCP1 expression stratifies patients with poor prognosis and therapy resistance across multiple cancer types. Our findings illuminate a previously unrecognized moonlighting function of SYCP1 in somatic cancer cells and position it as a critical chromatin-associated regulator of genome stability, with implications for biomarker development and therapeutic targeting.