Li Lan, MD, PhD

Associate Professor


Dr. Lan

Contact

412-623-3228
Fax: 412-623-7761

2.6 Hillman Cancer Center

5117 Centre Avenue

Pittsburgh, PA 15213-1862

Education

MD, Tohuku University, Sendai (Japan)

PhD, Tohuku University, Sendai (Japan)

Research Summary

My research has a primary focus on the mechanisms by which cells maintain genome stability against oxidative stress and its impact on aging and cancer, employing various aspects of basic cell biology, state-of-the-art live cell imaging techniques and animal models. Currently, our primary research foci are: (1) Transcription-coupled oxidative DNA damage response and human diseases; and (2) The telomere’s response to oxidative DNA damage and cancer. A growing body of evidence supports the role of oxidative stress in several key steps of the pathogenesis of many neurodegenerative diseases and tumorigenesis. DNA double strand breaks (DSBs) are a frequent and severe consequence of oxidative damage caused by many environmental chemicals, radiation, and normal metabolism. Most likely, DSBs lead to genomic abnormalities that underpin the degenerative neurological diseases and tumorigenesis arising in terminally differentiated (G0) cell populations. At active transcription sites, RNA Polymerase II (RNA POLII) can bypass DNA base modifications but not DNA single strand breaks (SSBs) or DSBs. We have been focused on understanding how deficiencies in genome maintenance in non-dividing somatic cells can lead to degenerative neurological diseases, as well as cancer, arising from seemingly stable G0 cell populations. My group has aimed to reveal how transcription-coupled DNA repair mechanisms contribute to genome stability and prevent the clinical features otherwise observed in DNA repair-deficient patients with developmental defects and neurological degeneration. We developed the DNA Damage at RNA Transcribed sites (DART) system (Mol Cell 2010, NAR 2014), which is a unique and precise approach that allows oxidative DNA damage to be introduced at a specific transcribed region in a dose-dependent manner. Recently, our research led to the discovery of a novel RNA-templated HR mechanism of DSB repair at active transcription sites in G0/G1 cell populations (PNAS 2015), which is very important in deciphering the interactions between genetic susceptibility and environmental factors that damage DNA. This discovery will likely lead to a new paradigm that explains how cells protect DNA damage in coding regions and how DNA repair defects give rise to degenerative pathologies. In the future, we aim to elucidate the mechanism by which DSBs are channeled into the RNA-templated recombinational repair process. The other long-term goal of my research is to understand how cancer cells achieve replicative immortality since telomeres get shorter during the cell division process in normal cells and this contributes to aging, but stay relatively stable in cancer cells. Due to the unique chromatin structure of the telomere, the consequences of oxidative DNA damage and the resulting repair mechanisms may differ between telomeres and non-telomeric DNA. My group has made a breakthrough with a novel technique for introducing oxidative damage specifically at the telomeres in a highly controlled manner and discovered the mechanisms for telomere maintenance in cancer cells (NAR 2015, Mol Cell 2017). Given the importance of telomeres in stem cell self-renewal, pursuing the regulating mechanisms of telomere maintenance will also have a broad impact on advancing research on organogenesis, tissue regeneration, and aging, as well as providing a potential drug discovery platform to develop new chemo- and radio-sensitizing agents.

Research Lab Affiliation

Publications

Tan R, Nakajima S, Zeng X, Yates N, Smithgall TE, Lei M, Jiang Y, Levine AS, Su B and Lan L. (2017) Nek7 protects telomeres from oxidative DNA damage by phosphorylation and stabilization of TRF1. Mol Cell. [in press] |  

Sun L, Nakajima S, Teng Y, Chen H, Yang L, Chen X, Gao B, Levine AS, Lan L. (2017) WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1. Nucleic Acids Res. |  View Abstract

Yang L, Sun L, Teng Y, Chen H, Gao Y, Levine AS, Nakajima S, Lan L. (2017) Tankyrase1-mediated poly(ADP-ribosyl)ation of TRF1 maintains cell survival after telomeric DNA damage. Nucleic Acids Res. |  View Abstract

Gao Y, Li C, Wei L, Teng Y, Nakajima S, Ma H, Spagnol ST, Leger B, Wan Y, Dahl KN, Liu Y, Levine AS, Lan L. (2017) SSRP1 cooperates with PARP and XRCC1, facilitating single strand break repair through chromatin priming. Cancer Res. (In press) |  

Wei L, Nakajima S, Bohm S, Bernstein KA, Shen Z, Tsang M, Levine AS and Lan L. (2015) DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination. Proc Natl Acad Sci USA. 112: E3495-E3504. |  View Abstract

Sun L, Tan R, Xu J, LaFace J, Gao Y, Xiao Y, Attar M, Neumann C, Li GM, Su B, Liu Y, Nakajima S, Levine AS and Lan L. (2015) Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death. Nucleic Acids Res. 43: 6334-6347. |  View Abstract

Wei, L; Nakajima, S; Hsieh, C.L; Kanno S; Masutani, M; Levine, A.S; Yasui, A and Lan L. (2013) Damage response of XRCC1 at sites of DNA single strand breaks is regulated by phosphorylation and ubiquitylation after degradation of poly(ADP-ribose). J Cell Sci.126: 4414-4423. |  View Abstract