Alteration in cell cycle and actin dynamics as a potential underlying cause of Cockayne syndrome

초록

Human XPG gene encodes a well-known DNA repair related endonuclease that specifically cleaves the 3’ side of a DNA lesion. RAD2, a yeast homolog of XPG, is also known to be involved in transcription elongation in addition to DNA repair. Defects of XPG gene cause xeroderma pigmentosum (XP) and/or Cockayne syndrome (CS), two distinct hereditary human disorders. XP is characterized by increased UV sensitivity and predisposition of cancer incidence due to the accumulation of damaged-DNA, while CS is characterized by growth retardation, neurological abnormalities, and premature aging without increased cancer rate. Transcriptional defects have been suggested as the cause of CS, but it is still elusive. Using yeast genetics, we have examined a novel function of RAD2 in CS. We have found evidence for the involvement of RAD2 in cell cycle regulation and efficient actin assembly following UV irradiation. RAD2 C-terminal deletion, which resembles the XPG mutation found in XP/CS patient cells, caused cell growth arrest, the cell cycle stalling, a defective alpha-factor response, shortened lifespan, cell polarity defect, and misregulated 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 incidence in the presence of DNA damage in CS patients.