ABL1-mediated tyrosine phosphorylation of SYCP2 contributes to transcription-coupled homologous recombination and platinum resistance in ovarian cancer.
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2025-09
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Abstract
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 in vivo. 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.
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Gao, Boya, Xudong Wang, Melissa Long, Fengqi Zhang, Yumin Wang, Raj Kumar, Irva Veillard, Bo R Rueda, et al. (2025). ABL1-mediated tyrosine phosphorylation of SYCP2 contributes to transcription-coupled homologous recombination and platinum resistance in ovarian cancer. NAR cancer, 7(3). p. zcaf031. 10.1093/narcan/zcaf031 Retrieved from https://hdl.handle.net/10161/33254.
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Scholars@Duke
Li Lan
The Lan Lab is dedicated to researching how cancer cells respond to DNA damage through DNA repair mechanisms and developing innovative strategies to target these pathways in cancer therapy. Our significant contributions include uncovering the critical role of PARP in DNA repair, leading to successful applications of PARP inhibitors in the treatment of breast, ovarian, and other types of cancer. We study how DNA responds to oxidative damage at specific chromosomal locations, significantly advancing our understanding of DNA damage response in different chromosomal environments. Furthermore, our recent investigations have revealed a novel mRNA and R-loop-dependent DNA repair pathway that acts as a protective mechanism for the transcribed regions of the genome, introducing a new paradigm in the field of DNA repair research.
Some of the research interests of the Lan Lab:
- Unraveling the underlying mechanisms of mRNA and R-loop-dependent DNA repair (RDDR) in cancer and developing targeted therapies. We actively investigate the molecular mechanisms of the RDDR pathway, including its regulators. We study how the pathway is processed coupling with DNA replication and chromatin remodeling. We employ screening platforms to monitor the RDDR pathway and the function of RDDR proteins, with the goal of developing inhibitors that disrupt RDDR in cancer cells. We try to identify RDDR biomarkers for patient stratification and predict the response to RDDR-targeted therapy. Additionally, we explore its potential applications in gene editing. Our research spans from basic science to translation, with a focus on the potential of mRNA-modifying enzymes as therapeutic targets for treating cancers exhibiting increased genome instability.
- Investigating the response of telomeres to oxidative damage in cancer and exploiting vulnerabilities in cancer cells. By comprehending how cancer cells respond to oxidative damage at telomeres through mechanisms such as telomerase, alternative lengthening of telomeres, and mRNA and R-loop-mediated repair pathways, our goal is to selectively eliminate cancer cells experiencing oxidative stress.
- Exploring the interplay between DNA damage response and immune response in cancer. Our investigations have shed light on the role of the DNA sensor cGAS in triggering the STING-dependent interferon response, subsequently modulating the tumor microenvironment to enhance anti-tumor immunity. Currently, we are examining how DNA damage and R-loops regulate the functions of cGAS in cancer cells. Through our mechanistic studies, we aim to provide a molecular basis for enhancing immune checkpoint blockade-mediated therapy by modulating specific cGAS functions in combination with RDDR targeted therapy.
Overall, the research conducted by the Lan Lab strives to advance our understanding of DNA repair processes in cancer and the role of RNA and R-loops in these processes. We are dedicated to translating our findings into innovative therapeutic strategies that have the potential to revolutionize cancer treatment and improve patient outcomes.
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