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

Yumin Wang, Boya Gao, Luyuan Zhang, Xudong Wang, Xiaolan Zhu, Haibo Yang, Fengqi Zhang, Xueping Zhu, Badi Zhou, Sean Yao, Aiko Nagayama, Sanghoon Lee, Jian Ouyang, Siang-Boon Koh, Eric L. Eisenhauer, Dominique Zarrella, Kate Lu, Bo R. Rueda, Lee Zou, Xiaofeng A. Su, Oladapo Yeku, Leif W. Ellisen, Xiao-Song Wang and Li Lan ()
Additional contact information
Yumin Wang: Massachusetts General Hospital Cancer Center, Harvard Medical School
Boya Gao: Massachusetts General Hospital Cancer Center, Harvard Medical School
Luyuan Zhang: Emory University School of Medicine
Xudong Wang: Massachusetts General Hospital Cancer Center, Harvard Medical School
Xiaolan Zhu: Massachusetts General Hospital Cancer Center, Harvard Medical School
Haibo Yang: Massachusetts General Hospital Cancer Center, Harvard Medical School
Fengqi Zhang: Massachusetts General Hospital Cancer Center, Harvard Medical School
Xueping Zhu: Massachusetts General Hospital Cancer Center, Harvard Medical School
Badi Zhou: Massachusetts General Hospital Cancer Center, Harvard Medical School
Sean Yao: Massachusetts General Hospital Cancer Center, Harvard Medical School
Aiko Nagayama: Massachusetts General Hospital Cancer Center, Harvard Medical School
Sanghoon Lee: University of Pittsburgh
Jian Ouyang: Massachusetts General Hospital Cancer Center, Harvard Medical School
Siang-Boon Koh: University of Bristol; University Walk
Eric L. Eisenhauer: 55 Fruit St, Massachusetts General Hospital
Dominique Zarrella: 55 Fruit St, Massachusetts General Hospital
Kate Lu: David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology
Bo R. Rueda: 55 Fruit St, Massachusetts General Hospital
Lee Zou: Massachusetts General Hospital Cancer Center, Harvard Medical School
Xiaofeng A. Su: David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology
Oladapo Yeku: Massachusetts General Hospital Cancer Center, Harvard Medical School
Leif W. Ellisen: Massachusetts General Hospital Cancer Center, Harvard Medical School
Xiao-Song Wang: University of Pittsburgh
Li Lan: Massachusetts General Hospital Cancer Center, Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45693-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45693-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45693-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().