Lifespan regulation by actin dynamics regulation and amino acids metabolism

초록

Main research interests of our lab are studies on basic mechanisms of aging. One of them is to study the cause of premature aging such as Cockayne syndrome (CS). RAD2, a yeast homolog of human XPG gene, is a nucleotide excision repair gene. Mutations in XPG gene cause xeroderma pigmentosum (XP) or CS depends on the mutations. XP is a human hereditary genetic disorder, that is characterized by photosensitivity and increased skin cancer incidence in sun exposed areas. On the other hand, CS is characterized by retarded growth, impaired neurological development, mental retardation, and premature aging. We have found the role of Rad2p-PCNA interaction in UV-induced mutagenesis. Mutagenesis regulation by Rad2p-PCNA interaction implicates that XPG-PCNA interaction might be the cause of high cancer incidence in XPG patients. We also reported that the Rad2p C-terminal region is pivotal for post-UV actin dynamics regulation. These results provide insights into the role of RAD2 in post-UV irradiation cell cycle regulation and actin assembly, which may be an underlying cause of XPG/CS. Another main research interest of my lab is to study the role of amino acids metabolism on the regulation of yeast lifespan. Using metabolomics and genetic approaches, we identified metabolites affecting calorie restriction (CR)-induced chronological life span in yeast, Saccharomyces cerevisiae. Among 23 metabolites with altered profile by CR, we found that alanine level is inversely correlated with yeast chronological life span. Later analysis using deletion mutant of ALT1, the gene encoding the major alanine transaminase, revealed that life span modulation by ALT1 is TOR1-independent. Further studies showed that alt1Δ completely suppresses cytochrome C oxidase subunit 2 expression. This study shows the importance of small molecule metabolism and relevance of metabolomics combined with genetic approach in the mechanistic studies in life span.