Deficiency in the nuclease activity of xeroderma pigmentosum G in mice leads to hypersensitivity to UV irradiation.
Xeroderma pigmentosum (XP) is a human disorder which is characterized by hypersensitivity to sunlight and elevated incidence of skin cancer. The disease is caused by mutations in genes that encode components of the nucleotide excision repair pathway. The gene product of XP complementation group G (XPG) is a structure-specific endonuclease which makes an incision 3' to DNA photoproducts and other helix-distorting DNA adducts. In addition, the XPG protein has been implicated in transcription and repair of oxidative DNA damage. Moreover, XPG is capable of cleaving R loops in vitro, a potential intermediate during immunoglobulin heavy-chain class switch recombination. Due to its multiple functions, complete elimination of XPG in mice results in severe postnatal growth defects and premature death. To understand the contribution of the XPG nuclease activity to its function in vivo, we introduced a point mutation into the mouse XPG gene which inactivates the nuclease catalytic site but leaves the remainder of the protein intact. The XPG nuclease-deficient animals develop normally and exhibit no obvious defect in class switch recombination. However, the mutant mice are hypersensitive to UV irradiation. This phenotype suggests that the nuclease activity of XPG is required only for nucleotide excision repair and that other regions of the protein perform independent functions.
Tian
Ming
M
Children's Hospital, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Jones
David A
DA
Smith
Michele
M
Shinkura
Reiko
R
Alt
Frederick W
FW
D000818:Animals; D001483:Base Sequence; D004260:DNA Repair; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D004720:Endonucleases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D017578:Immunoglobulin Class Switching; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins; D010641:Phenotype; D017354:Point Mutation; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D014157:Transcription Factors; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014983:Xeroderma Pigmentosum / Q000201:enzymology* / Q000235:genetics; D000099250:DNA Excision Repair Protein ERCC-5
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5