Biochemistry & Molecular Biology
Keck School of Medicine of USC
- Genome instability and cancer
Research OverviewDr. Guo-Min Li studies genome instability and cancer, with a focus on DNA mismatch repair (MMR), an important cellular pathway that ensures replication fidelity by correcting mispairs created during DNA replication. Dr. Li has made seminal contributions to the field, including discovering MMR defects in colorectal tumors displaying microsatellite instability (MSI), identifying and characterizing the majority of human MMR components, reconstituting the human MMR reaction in vitro, and identifying the apoptotic function of MMR.
Although defects in MMR lead to a mutator phenotype characterized by MSI and an elevated mutational rate, a substantial fraction (~15%) of MSI-positive cancers do not have detectable mutations or abnormal expressions of MMR genes, suggesting that additional factors can also cause MSI-positive cancers. Recently, Dr. Li’s laboratory has made two striking observations, which provide novel clues to the long-standing puzzle. First, they demonstrate that the epigenetic histone mark H3K36me3 regulates MMR. In this case, H3K36me3 recruits mismatch recognition protein MutS to replicating chromatin by specifically interacting with the PWWP domain of MutS. This interaction is essential for MMR in vivo, as defects in either the PWWP domain or H3K36me3 lead to MSI and an elevated mutation rate. Second, they find that PCNA phosphorylation by epidermal growth factor receptor (EGFR) family tyrosine kinases inhibits MMR, providing the molecular clues as to why cancer progression is associated with overexpression of EGFR family tyrosine kinases and increased genome instability.
These novel findings have prompted Dr. Li’s laboratory to study how epigenetic and posttranslational modifications regulate MMR, genome stability, and cancer etiology and development. His laboratory is studying 1) the mechanism by which PCNA phosphorylation inhibits MMR and promotes tumor progression using cell line and animal models; and 2) the distribution and abundance of the H3K36me3 mark in chromatin and their implication in gene mutations and cancer development.
Dr. Li is also very interested in targeting MMR factors for cancer therapy. Recently, his laboratory has created two novel mutant MMR molecules, which have potential to be effective drugs for cancer treatment. One molecule is a defective MutS, and the other is a phosphorylation-mimicking PCNA. They show that the mutant MutS can effectively initiate the MMR reaction, but it blocks MMR at the excision stage, generating a long ssDNA region and leading to cell death. Thus, the mutant MutS may specifically kill MMR-deficient cancer cells, as these cells produce numerous mispairs during DNA replication. They also find that a phosphorylation-mimicking PCNA kills cells. Dr. Li’s laboratory is testing cancer-killing ability of these novel mutant MMR proteins in cell line and xenograft models.
A second research area in Dr. Li's laboratory is to study the mechanism by which the MMR system promotes trinucleotide repeat (TNR) expansion, which cause at least 17 different neurodegenerative disorders, including Huntington’s disease, fragile X and myotonic dystrophy. Dr. Li's recent studies in TNR instability have led to the discovery of a novel DNA repair pathway (referred to as DNA hairpin repair) that is responsible for stabilizing (CAG)n/(CTG)n repeats. They are in the process of identifying and characterizing activities required for this repair pathway. This work will provide significant insight into the pathogenesis underlying neurodegenerative diseases associated with TNR expansions.