Li Lan, MD, PhD
Assistant Professor in Radiation Oncology
Massachusetts General Hospital Cancer Center
Harvard Medical School
Center for Cancer Research
Explore the Lan Lab
Oxidative DNA damage and replication stress are major sources of genomic instability during tumorigenesis and aging. The main research goal of the Lan laboratory is centered on the mechanisms by which human cells maintain genomic stability against oxidative and replication stresses. Elevated oxidative and replication stresses have been detected in almost all cancers, and these stresses promote many aspects of cancer including tumorigenesis, tumor progression, and drug responses. We are especially interested in understanding how cancer cells protect the transcribed regions upon increased stress level to survive, and are also studying telomere protection in cancer and cross talk between DDR and immune response. Our lab has developed the first single-cell assay to interrogate the molecular mechanisms of oxidative DNA damage response at distinct loci in the genome. We aim to open new avenues to understanding the oxidative DNA damage response in different chromosomal environments.
A growing body of evidence suggests that oxidative stress plays an important role in tumorigenesis and aging-related diseases. Oxidative stress caused by environmental insults and endogenous metabolites induces DNA base modifications and strand breaks. DNA strand breaks have detrimental effects not only on actively proliferating cells, but also on slowly proliferating cells and terminally differentiated cells. At active transcription sites, RNA Polymerase II can bypass DNA base modifications, but not strand breaks. Given the heterogeneity of cancer cells in tumors, it is critical to understand how dividing and non-dividing cells respond to oxidative DNA damage. One of the main research interests of the Lan laboratory is to understand how oxidative DNA damage response is differentially regulated in transcribed and un-transcribed regions, and in dividing and non-dividing cells. We discovered a novel mRNA-dependent and R loop-mediated homologous recombination (HR) mechanism that specifically promotes repair in the transcribed genome. Our work has revealed an unexpected role for mRNA in HR. Importantly, we show that this mRNA-mediated HR mechanism is able to operate even in G0/ G1 cells, challenging the current view that HR only occurs during the S/G2 phase of the cell cycle. Our findings may likely lead to a new paradigm in DNA repair, and to a better understanding of how actively proliferating and slowly proliferating cancer cells respond to oxidative damage. In the near future, we plan to address several important questions on this new pathway that we discovered:
- Whether and how is the RNA-mediated HR pathway distinct from the canonical HR pathway?
- How is repair “channeled” into the RNA-mediated HR pathway in transcribed regions?
- Is the RNA-mediated HR pathway important for tumor suppression?
In our ongoing studies, we are exploring the function of RNA modifications in the RNA-mediated HR pathway and screening small compounds to efficiently prohibit this pathway. We use animal models, bioinformatical approaches, and patient samples to assess the functional significance of RNA-mediated HR In Vivo. Going forward, we would like to expand our studies to investigate the status of this new RNA-mediated HR repair pathway in cancer cells, its potential function in tumor suppression, and its value as a therapeutic target.
Another research interest of the Lan laboratory is to explore the crosstalk between innate immune response and DNA damage response via cGAS-STING pathway in cancer cells. It is known that cGAS acts as the DNA sensor in the cytosol, which can be activated by binding to double-stranded DNA in a sequence-independent manner. This DNA binding of cGAS triggers STING-dependent innate immune response. Although the role of cGAS in immunity is well established, whether and how cGAS functions in other cellular processes remain elusive. We are focused on how the function of cGAS in the nucleus regulates replication, transcription and how DNA damage response is related with tumorigenesis.
A third research priority of our lab is to understand how telomeres respond to oxidative DNA damage. Telomere dysregulation is a major source of genomic instability and a potential target for cancer therapy. Due to G/C-rich telomeric repeats, telomeres are particularly vulnerable to oxidative stress. Interestingly, telomeres are protected by specific “capping” proteins, making DNA damage response at telomeres significantly different from elsewhere in the genome. More specifically, we are investigating the possibility of whether oxidative damage at telomeres triggers telomere attrition, senescence, and the promotion of tumorigenesis. Our lab has established a new method to introduce oxidative damage at telomeres in a highly controlled manner, allowing us, for the first time, to specifically follow the oxidative damage response at telomeres. In several projects, we have investigated how HR factors are regulated by shelterin proteins at telomeres during the oxidative damage response. The recruitment of repair factors to telomeres is coordinately regulated by poly-ADP-ribosylation, phosphorylation, SUMOylation, and ubiquitylation of TRF1 to protect cancer cells from telomere damage. Our future goal is to investigate whether and how the mechanisms orchestrating oxidative damage response at telomeres may contribute to the suppression of tumorigenesis and aging, and how we can exploit this specific vulnerability of cancer cells in therapy.
Postdoctoral/Lab Technician Positions
Postdoctoral/lab technician positions are available in the Lan Lab. We are studying mechanisms of DNA damage response that are relevant to tumorigenesis, aging, and effective therapeutic approaches for cancer. For Postdoctoral positions, candidates who are interested in DNA damage and cancer with a PhD and/or MD degree, and with experience in biochemical, cell biological, genetic, imaging, bioinformatics, or animal research are encouraged to apply.
Please send a CV with past research experience and the contact information of three references to Li Lan at Llan1@mgh.harvard.edu.
Chen H, Chen H2, Zhang J, Wang Y, Simoneau A, Yang H, Levine AS, Zou L, Chen Z, and Lan L. cGAS Suppresses Genomic Instability as a Decelerator of Replication Forks. Science Advances, 2020, in press
Chen H, Yang H, Zhu X, Yadav T, J, Zou L, Levine AS, Vasudevan S, Lan L. m5C Modification of mRNA Serves a DNA Damage Code to Promote Homologous Recombination. Nature Communications. 2020 June 5th. 11, 2834. Featured article
Tan J, Wang X, Phoon L, Yang H, Lan L. Resolution of ROS-induced G-quadruplexes and R-loops at transcriptionally active sites is dependent on BLM helicase. FEBS Lett. 2020 May;594(9):1359-1367. Featured article
Tan J, Duan M, Yadav T, Phoon L, Wang X, Zhang JM, Zou L, Lan L. An R-loop-initiated CSB-RAD52-POLD3 pathway suppresses ROS-induced telomeric DNA breaks. Nucleic Acids Res. 2020 Feb 20;48(3):1285-1300.
Teng Y, Yadav T, Duan M, Tan J, Xiang Y, Gao B, Xu J, Liang Z, Liu Y, Nakajima S, Shi Y, Levine AS, Zou L, Lan L. ROS-Induced R Loops Trigger a Transcription-Coupled but BRCA1/2-Independent Homologous Recombination Pathway through CSB. Nature Communications, in press.
Tan R, Nakajima S, Wang Q, Sun H, Xue J, Wu J, Hellwig S, Zeng X, Yates N, Smithgall TE, Lei M, Jiang Y, Levine AS, Su B, Lan L. Nek7 protects telomeres from oxidative DNA damage by phosphorylation and stabilization of TRF1. Mol Cell. 2017 Mar 2;65(5):818-831.e5.
The Lan laboratory developed the DNA Damage at RNA Transcribed sites (DART) method to precisely introduce oxidative DNA damage at specific transcribed loci in a dose-dependent manner.
This is achieved by site-specific positioning of the photo-excitable and ROS-releasing protein KillerRed (KR). This unique method provides a tool to understand how oxidative DNA damage response is differentially regulated in transcribed and un-transcribed regions, & in dividing & non-dividing cells.
Li Lan, MD, PhDPrincipal Investigator
- Boya Gao, technician
- Laiyee Phoon, technician
- Xiangyu Wang, MD
- Yao Xiao, MD
- Haibo Yang, PhD