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:

1. 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.
2. 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.
3. 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.

• Wang, Yumin, Boya Gao, Luyuan Zhang, Xudong Wang, Xiaolan Zhu, Haibo Yang, Fengqi Zhang, et al. “Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.” Nat Commun 15, no. 1 (February 21, 2024): 1568. https://doi.org/10.1038/s41467-024-45693-2.
• Lakkaniga, Naga Rajiv, Zhengyu Wang, Yao Xiao, Anupreet Kharbanda, Li Lan, and Hong-Yu Li. “Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy.” Med Res Rev 44, no. 2 (March 2024): 686–706. https://doi.org/10.1002/med.21994.
• Wang, Yumin, Boya Gao, Luyuan Zhang, Xudong Wang, Xiaolan Zhu, Haibo Yang, Fengqi Zhang, et al. “Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.” Nat Commun 15, no. 1 (February 21, 2024): 1568. https://doi.org/10.1038/s41467-024-45693-2.
• Wang, Mingchao, Xiaojuan Ran, Wendy Leung, Ajinkya Kawale, Sneha Saxena, Jian Ouyang, Parasvi S. Patel, et al. “ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.” Genes Dev 37, no. 19–20 (October 1, 2023): 929–43. https://doi.org/10.1101/gad.351084.123.
• Yang, Haibo, Emily M. Lachtara, Xiaojuan Ran, Jessica Hopkins, Parasvi S. Patel, Xueping Zhu, Yao Xiao, et al. “The RNA m5C modification in R-loops as an off switch of Alt-NHEJ.” Nat Commun 14, no. 1 (September 30, 2023): 6114. https://doi.org/10.1038/s41467-023-41790-w.
• Petermann, Eva, Li Lan, and Lee Zou. “Sources, resolution and physiological relevance of R-loops and RNA-DNA hybrids.” Nat Rev Mol Cell Biol 23, no. 8 (August 2022): 521–40. https://doi.org/10.1038/s41580-022-00474-x.
• Yang, Haibo, Yumin Wang, Yufei Xiang, Tribhuwan Yadav, Jian Ouyang, Laiyee Phoon, Xueping Zhu, Yi Shi, Lee Zou, and Li Lan. “FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation.” Proc Natl Acad Sci U S A 119, no. 12 (March 22, 2022): e2116251119. https://doi.org/10.1073/pnas.2116251119.
• Yang, Haibo, and Li Lan. “Immunostaining and Protein Pull-Down of Methyl-5-Cytosine-Marked RNA:DNA Hybrids.,” 2528:271–76, 2022. https://doi.org/10.1007/978-1-0716-2477-7_17.

To see a complete list of publications, please visit: https://www.ncbi.nlm.nih.gov/myncbi/li.lan.2/bibliography/public/