HomeResearchIntramural ResearchResearch Branches at NHGRIGenetics and Molecular Biology Branch Myung Lab

Kyungjae Myung, Ph.D. Investigator Genetics and Molecular Biology Branch Head Genome Instability Section B.S. Seoul National University, 1991 M.S. Seoul National University, 1993 Ph.D. Brown University, 1999 (301) 451-8748 (301) 402-4929 kmyung@nhgri.nih.gov Building 49, Room 4A22 49 Convent Dr, MSC 4442 Bethesda, MD 20892-4442 Selected Publications

Dr. Myung's laboratory investigates genome instability, which is found in many genetic disorders, including cancer. Different types of genome instability have been identified. They include the accumulation of mutations, chromosomal rearrangements and aneuploidy (an abnormal number of chromosomes). These defects have been linked to faulty DNA repair and DNA damage responses. Many of them are seen in the chromosomes of tumors from people with mutations in DNA repair genes, indicating that genetic instability defects are probably precursors to tumor development.

Dr. Myung's group is investigating DNA repair, replication and recombination mechanisms and their roles in the production and suppression of gross chromosomal rearrangements (GCRs). Specifically, his group is looking at how previously identified mutator genes regulate the process of genome instability and is trying to find unidentified genes encoding proteins that suppress genome instability. They are also trying to develop new model systems to study genome instability.

Using a whole-genome screening method developed by Dr. Myung, his laboratory is studying some of the pathways that maintain genome stability and, when perturbed, contribute to the occurrence of GCRs. Recently, in a genome-wide screen of yeast, his group identified ten more genes that encode proteins that suppress GCRs. They recently characterized the mechanism of action of three of these GCR-suppressing genes: ELG1, RAD5 and RAD18.

The group has found that the Elg1 protein is involved in DNA repair and the elg1Δ mutation enhances spontaneous DNA damage, which results in GCR formation. They have also found that DNA damage produced by inactivating the Elg1 protein will, in turn, activate a feedback mechanism called the intra-S checkpoint that further suppresses GCR formation. Interestingly, they discovered that the elg1Δ mutation increases telomere size independently of other previously known telomere maintenance proteins, and when they knocked out the ELG1 gene in a mammalian system and used ELG-1-specific interfering RNA to suppress ELG1 expression in another set of experiments, they found that mammalian ELG1 shares similar functions with yeast Elg1.

Dr. Myung's group also found that GCRs are suppressed by a template switching mechanism composed of a post-replication repair pathway principally regulated by Rad18- and Rad5-dependent PCNA polyubiquitination. They discovered that, in the absence of this template switching mechanism, GCR formation was caused by Siz1-dependent PCNA sumoylation and Srs2 helicase recruitment. The group also recently identified two mammalian RAD5 genes, called SHPRH and HLTF, that the scientific community has been trying to find for 20 years. SHPRH and HLTF also promote PCNA polyubiquitination and suppress GCR formation and were found in the mutations of several cancer cells.

Dr. Myung's group recently identified many genes that enhance GCR formation when overexpressed in yeast. MPH1, the gene that enhanced GCR formation the most among all the genes the group identified, is a yeast Fanconi Anemia class M gene homolog. Mph1 overexpression enhanced GCR formation by partially inactivating Rad52-dependent homologous recombination.

Several early-stage investigations into other potential enhancers of GCRs are being conducted in Dr. Myung's laboratory. In one of these studies, his group is investigating how the overexpression of Spt2, which functions integrally with transcription machinery, increased GCRs. They are also using knockout mouse models of RAD5 and ELG1 to determine if these genes are involved in tumor formation, and trying to create new ways to measure GCR formation in mammals when DNA replication is challenged.

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Last Updated: April 8, 2008