Distinguished Teaching Professor
Cell Cycle; Cell growth, differentiation and development; Gene Expression; Inherited Metabolic Disorders; Molecular Basis of Disease; Protein Function and Structure; Proteins and metalloenzymes
Protein Methylation in Growth and Differentiation.
Protein methylation was recently found by systems biology approaches to play a major role in regulating yeast cell growth. Consistent with this finding, we found that disruption of the gene encoding S-adenosylhomocysteine (SAH1) hydrolase markedly inhibited growth. S-adenosylmethionine (SAM) is the universal methyl donor,and SAH1 is the product of all methyltransferase(MTase) reactions.The SAH1 disruption leads to a 50% decrease in protein synthesis which,in turn leads to major decreases in the levels of Cln3p.Unexpectedly,when cells were transfected with a modified gene for Cln3 ,that desreased its rate of degradation,growth rates were normal.This result was unexpected because the basic defect of lacking SAH1 remained.We are currently testing the hypothesis that normal rates of growth are due to increased gene expression for multiple enzymes known to be involved in Met and SAM synthesis. We are also identifying substrates for specific MTases in yeast.
Copper deficiency is known to affect brain development, and Menkes disease is fatal due to impaired brain development from low brain copper. A reduction in (SAH1) levels, as occurs in copper deficiency, may affect brain development by inhibiting protein methylation.We demonstrated that inhibiting SAH1 maredly inhibited development of two nerve cell models.