CIMR-Guo-Min Li

Research Group

Guo-Min Li

gmli(at)cimrbj.ac.cn

Distinguished Investigator

gmli(at)cimrbj.ac.cn

B.S. in Department of Biology, Wuhan University, China

M.S. in Department of Biology, Wuhan University, China

Ph.D. in Department of Chemistry, Wayne State University, USA

Work Experience

2023-present

Distinguished Investigator and Director, Institute for Cancer Research, Chinese Institutes for Medical Research, Beijing, China

2023-present

Chair Professor, Capital Medical University, China

2017.6-2022

Director, the Reece A. Overcash Jr. Center for Research on Colon Cancer, UT Southwestern Medical Center (UTSW), USA

2017.6-2022

Director of Translational Research, Department of Radiation Oncology, UT Southwestern Medical Center (UTSW), USA

2017.6-2022

Professor and the Reece A. Overcash Jr. Distinguished Chair in Cancer Research, Department of Radiation Oncology, UT Southwestern Medical Center (UTSW), USA

2015.8-2017.5

Professor and Jane & Kris Popovich Distinguished Chair in Cancer Research, Department of Biochemistry & Molecular Biology, University of Southern California Keck School of Medicine, USA

2006-2015.7

Professor, Department of Toxicology and Cancer Biology, University Kentucky, USA

2001-2015.7

Madeline F. James & Edith D. Gardner Distinguished Chair in Cancer Research, University Kentucky, USA

2000-2005

Associate Professor, Department of Pathology, University Kentucky, USA

1995-1999

Assistant Professor, Department of Pathology, University Kentucky, USA

1991-1995

Postdoc, Duke University, Durham, North Carolina, USA Adviser: Dr. Paul Modrich (Nobel laureate, Chemistry 2015)

Research Direction

We are broadly interested in cellular mechanisms maintaining genome stability and their implications in human diseases and therapies, with particular interests in cancer and neurodegenerative disorders.

Major Research Projects

1. Mechanistic studies of DNA mismatch repair

DNA mismatch repair (MMR) maintains genome stability by primarily correcting DNA replication errors in the newly synthesized strand. Defects in MMR leads to cancer and other human diseases. The MMR reaction has been reconstituted, which involves mismatch recognition by MutS family proteins (MutS in prokaryotes, and MSH2MSH6-formed MutS or MSH2MSH3-formed MutS in eukaryotes), removal of the mispaired base by nucleases in a manner dependent on MutS- and MutL-family proteins, and repair DNA synthesis by a replicative DNA polymerase in concert with DNA replication factors. Despite extensive studies, many fundamental questions in MMR are still unknown.

1). How is MMR specifically targeted to the newly-synthesized strand?
Unlike the obvious DNA lesions for other DNA repair pathways, both bases in a mismatch (e.g., mispaired GT or CA) are normal DNA components. Thus, to remove the incorrect base, the MMR system has to know the wrong information-containing daughter strand. Previous studies have revealed that DNA strand breaks in the newly synthesized daughter strand serve as a strand discrimination signal, ensuring the repair specifically targeted to the daughter strand. However, a strand break is usually several hundred base pairs away from a mismatch, how these two distal sites communicate with each other during MMR has been a standing puzzle in the field. Dr. Li’s lab has reconstituted the human MMR reaction in a defined system. Using this reconstituted system, The Li laboratory aims to resolve this fundamental but important problem in MMR.

2). How does MMR occur in vivo?

Our knowledge about the mechanism of MMR essentially came from the in vitro studies using naked DNA heteroduplexes. However, DNA is packed into nucleosome-consisting chromatin in vivo. How MMR occur in vivo is largely unknown. Dr. Li’s lab has shown that MutS is recruited to replicating chromatin through its physical interaction with H3K36me3 (histone H3 lysine 36 trimethylation). Consistent with this observation, disrupting the MutS-H3K36me3 interaction leads to a mutator phenotype similar to that of cells defective in MMR genes. How are other MMR proteins recruited to chromatin? How do they interact with each other in vivo? Understanding these questions will provide critical information for clinical practice, including cancer diagnosis and therapy. Using cutting-edge technologies, the Li Lab is studying the in vivo MMR reaction.

2. Targeting mismatch repair for cancer therapy

Despite decades of extensive studies, cancer is still one of the leading causes of death in the world. The major problem is that essentially no therapies can fully eradicate the malignant clone and avoid of drug resistance and side effects. Cancer cells defective in MMR (dMMR) are highly resistant to many chemo- and radiation-therapeutic drugs. However, recent studies have shown that dMMR tumors respond very well to immunotherapy. However, the mechanism by MMR deficiency benefits immunotherapy is largely unknown. Dr. Li’s lab is studying the mechanism by which MMR deficiency triggers immunotherapy and developing methods to deplete the MMR activity in other cancers so that they can be treated with immunotherapy. In addition, his lab is also identifying/developing molecules specifically blocking MMR activity for cell killing. The latter project includes small molecules and altered MMR proteins capable of triggering cell death during MMR.

3. Mismatch repair in neurodegenerative diseases

Trinucleotide repeat expansions cause more than 30 severe neuromuscular and neurodegenerative disorders, including Huntington’s disease, myotonic dystrophy type 1, and fragile X syndrome. Although the MMR system is well known for its role in maintaining replication fidelity, key MMR proteins, especially MutSβ (MSH2-MSH3) and MutLg (MLH1-MSH3), have been implicated in promoting trinucleotide repeat instability. However, the molecular basis by which the MMR system causes trinucleotide repeat expansions is not known.

4. Resolving the structure of mismatch repair initiation complex

Crystal structure and Cryogenic electron microscopy (cryo-EM) studies have resolved numerous structures of proteins. Despite extensive efforts in the past, not all structures of MMR proteins have been determined. Resolving the structures of the individual MMR proteins, particularly that of the MMR initiation complex containing the mismatched DNA, MutS, MutL, PCNA, RPA and exonuclease 1, is quite challenging, but very important, as this will provide not only the mechanism of the MMR reaction, but also strategies for developing cancer therapeutical drugs.

Major Contributions

1. Discovered that MMR deficiency cause tumors with microsatellite instability (Cell, 1993)

2. Reconstituted the human MMR reaction using purified proteins (Cell, 2005, Cell Research, 2021)

3. Discovered histone mark H3K36me3 as a required factor for MMR in vivo (Cell, 2013)

4. Illustrated the molecular mechanism by which MMR-deficiency benefits cancer immunotherapy (Cancer Cell, 2021a; Cancer Cell, 2021b)

5. Illustrated the mechanism by which MutSβ promotes CAG/CTG repeat expansion (Cell Research, 2016)

Representative Publications *：Co-first author; #：Co-corresponding author

Huang Y, Gu L, Li GM. Heat shock protein DNAJA2 regulates transcription-coupled repair by triggering CSB degradation via chaperone-mediated autophagy. Cell Discovery, Accepted (2023). DOI: 10.1038/s41421-023-00601-8

Huang Y* , Lu C*, Wang H, Gu L, Fu YX^#, Li GM^#. DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability. Nature Communications, 2023, 14: 5246. DOI: 10.1038/s41467-023-40952-0

Zhang J, Zhao X, Liu L, Li HD, Castrillon DH, Gu L, Li GM. The mismatch recognition protein MutSa promotes nascent strand degradation at stalled replication forks. Proceedings of the National Academy of Sciences of the United States of America. 2022, 119: e2201738119. DOI: 10.1073/pnas.2201738119

Guan J*, Lu C*, Jin Q, Lu H, Chen X, Tian L, Zhang Y, Ortega J, Zhang J, Siteni S, Chen M, Gu L, Shay J, Davis A, Chen ZJ, Fu YX^#, Li GM^#. MLH1 deficiency-triggered DNA hyperexcision by exonuclease1 activates the cGAS-STING pathway. Cancer Cell, 2021, 39: 109-121. DOI: 10.1016/j.ccell.2020.11.004

Lu C*, Guan J*, Lu S, Jin Q, Rousseau B, Lu T, Stephens D, Zhang H, Zhu J, Yang M, Ren Z, Liang Y, Liu Z, Han C, Liu L, Cao X, Zhang A, Qiao J, Batten K, Chen M, Castrillon DH, Li B, Li GM^#, Fu YX^#. DNA sensing in mismatch repair-deficient tumor cells is essential for anti-tumor immunity. Cancer Cell, 2021, 39: 96-108. DOI: 10.1016/j.ccell.2020.11.006

Ortega J*, Lee GS*, Gu L, Yang W, Li GM. Mispair-bound human MutS-MutL complex triggers DNA incisions and activates mismatch repair. Cell Research, 2021, 31: 542-553. DOI: 10.1038/s41422-021-00468-y

Huang Y*, Zhao J*, Mao G, Lee GS, Zhang J, Bi L, Gu L, Chang Z, Valentino J^#, Li GM^#. Identification of novel genetic variants predisposing to familial oral squamous cell carcinomas. Cell Discovery, 2019, 5: 57. DOI: 10.1038/s41421-019-0126-6

Fang J*, Huang Y*, Mao G*, Yang S, Rennert G, Gu L, Li H, Li GM. Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutSa. Proc Natl Acad Sci USA, 2018, 115: 9598-9603. DOI: 10.1073/pnas.1806355115

Guo J, Gu L, Leffak M, Li GM. MutSβ promotes trinucleotide repeat expansion by recruiting DNA polymerase β to nascent (CAG)n or (CTG)n hairpins for error-prone DNA synthesis. Cell Research, 2016, 26: 775-786. DOI: 10.1038/cr.2016.66

Li F, Mao G, Tong D, Huang J, Gu L^#, Yang W, Li GM^#. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell, 2013, 153: 590-600. DOI: 10.1016/j.cell.2013.03.025