Alteration in cell cycle regulation can be the underlying cause of Cockayne syndrome

초록

RAD2, a yeast counterpart of human XPG gene, encodes a well known DNA repair related endonuclease that specifically cleaves the 3’ side of a DNA lesion. RAD2 is also known to be involved in transcription elongation. 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, neuronological 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. Over-expression of RAD2, which mimics induction of RAD2 expression in response to DNA damage, caused cell cycle arrest. Further analysis revealed that the C-terminal region of Rad2p is responsible for cell cycle arrest. Later, we examined the phenotypes of rad2 C-terminal deletion mutant (rad2CΔ) that resembles the C-terminal truncation of XPG in XPG/CS patients caused alteration in cell cycle after irradiation of ultra violet (UV) light. rad2CΔ mutant exhibits abnormal cell morphology, a defective α-factor response, shortened lifespan and cell polarity defect. These results implicate that post-UV cell cycle arrest due to the C-terminal truncation is the fundamental cause of XPG/CS.