Yunfu Lin, Ph.D.
Department of Biochemistry and Molecular Biology
- B.A., Beijing Normal University, 1982
- M.S., Beijing Normal University, 1985
- Ph.D., Fudan University, 1993
My research interest focuses on understanding the mechanisms of CAG repeat (CTG repeats on the complementary strand) instability using model systems in culture human cells and mice. Expansion of CAG repeat tracts within the human genome causes several neurological diseases such as Huntington's disease, myotonic dystrophy, and several spinocerebellar ataxias. However, the mechanisms leading to repeat instability, as well as disease pathogenesis, are ill-defined. The repeats are unstable in both germline and somatic cells, typically biased to expansion (increasing the number of repeats).
Recently, we showed for the first time that transcription can promote CAG repeat instability in human cells. Transcription-induced instability requires the mismatch repair component MutSβ (MSH2/MSH3 complex) and the entire transcription-coupled nucleotide excision repair pathway. In addition, we found that transcription-induced repeat instability is modulated by several pathways, including epigenetic modification (such as DNA methylation), DNA supercoiling, RNA/DNA hybrids, single-strand break repair, and protein chaperones (such as HSP90). Moreover, we found that antisense transcription can also promote repeat instability, with similar efficiency as sense transcription. Repeat instability is induced synergistically by simultaneous turn-on of sense and antisense transcription (i.e., convergent transcription).
Beyond stimulating repeat instability, convergent transcription through a CAG repeat tract leads to cell-cycle arrest and massive cell death via apoptosis in culture cells. These effects depend on the level of convergent transcription, as well as the length of the CAG repeats. Convergent transcription triggers a process that resembles the DNA damage response. It activates the cellular ATR pathway, including phosphorylation of ATR, CHK1, and p53. This phenomenon is exciting because it shows that apoptosis can be triggered by convergent transcription at a single site in the genome. This novel "DNA toxicity" may be relevant to the pathogenesis of disorders caused by CAG expansion, which often lead to cell death and neurodegeneration. We are currently investigating the mechanisms of transcription-induced repeat instability and possible link between convergent transcription-induced apoptosis and disease pathogenesis.