A role of yeast RAD2, a homolog of human XPG, in the regulation of the cell cycle and actin dynamics

초록

Cells exposed to DNA damaging agents express many genes to arrest the cell cycle progression and deal with DNA damage. Cell cycle arrest is commonly accompanied by cell polarity arrest, which is required for morphogenesis and development in higher eukaryotes. Therefore, unattainable re-initiation of the cell cycle from damage-induced cell cycle arrest is not possible growth and viability. In addition, cells with a compromised DNA repair system are confronted with irreversible mutations that can result in deleterious events such as cell death, aging, and cancer. Interestingly, Cockayne syndrome (CS) symptoms such as growth retardation and premature aging, can arise when cell cycle progression is hampered. Mutations in the human XPG gene cause CS and xeroderma pigmentosum. Transcription defects have been suggested as the fundamental cause of CS; however, defining CS as a transcription syndrome is inconclusive. In particular, the function of XPG in transcription has not been clearly demonstrated. Here, we provide evidence for the involvement of RAD2, the Saccharomyces cerevisiae counterpart of XPG, in cell cycle regulation and efficient actin assembly following ultraviolet irradiation. RAD2 C-terminal deletion, which resembles the XPG mutation found in XPG/CS cells, caused cell growth arrest, the cell cycle stalling, a defective α-factor response, shortened lifespan, cell polarity defect, and mis-regulated actin-dynamics after DNA damage. Over-expression of the C-terminal 65 amino acids of Rad2p was sufficient to induce hyper-cell polarization. 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. The arrested cell division and decreased lifespan of rad2C65Δ mutant cells after UV exposure suggest that the C-terminally truncated XPG protein in XPG/CS cells causes cell cycle arrest and decreased cell longevity, and this resulted in the absence of increased cancer