title: Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg.
abstract: In addition to xeroderma pigmentosum (XP), mutations in the human XPG gene cause an early onset of Cockayne syndrome (CS) in some patients (XP-G/CS) with characteristics, such as growth retardation and a short life span. In the previous studies, we generated four Xpg mutant mice with two different C-terminal truncations, null, or a base substitution mutation to identify the protein region that causes the onset of CS, and found that the CS-causing mutations, null or a deletion of the last 360 amino acids, completely inhibited the NER activity of mouse XPG (Xpg), but the non-CS-causing mutations, XpgD811A (base substitution that eliminates the nuclease activity of Xpg) or XpgDeltaex15 (deletion of the exon 15 corresponding to the last 183 amino acids), resulted in the retention of residual NER activity. To understand why mutations that completely eliminate the NER activity of Xpg cause CS but those that abolish the nuclease activity without totally eliminating the NER activity of Xpg do not result in CS, we made a series of Xpg mutant mice with Xpa-null mutant allele and found that mice with the non-CS-causing deletion mutation (XpgDeltaex15) exhibited the CS phenotype when XPA was also absent but the base substitution mutation (XpgD811A) that eliminated the Xpg nuclease activity did not. These results indicate that Xpg has a second function, beside NER, and that the disruption of this second function (deletion of the last 183 amino acids) when combined with an NER defect causes CS. When we compared amino acid sequences corresponding to the exon 15 of Xpg, a significant homology was conserved among vertebrates, but not in Drosophila and Saccharomyces cerevisiae. These observations suggest that the second function of XPG may be conserved only in vertebrates and CS symptoms may occur in its absence.
authors.affiliation: Research Center for Radiation Safety, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shiomi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mori
authors.forename: Seiji
authors.initials: S
authors.lastname: Kito
authors.forename: Yoshi-Nobu
authors.initials: YN
authors.lastname: Harada
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shiomi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004720:Endonucleases / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D005260:Female; D006128:Growth / Q000235:genetics*; D008017:Life Expectancy; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D018384:Oxidative Stress; D011836:Radiation Tolerance / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D051760:Xeroderma Pigmentosum Group A Protein; D000099250:DNA Excision Repair Protein ERCC-5; C497315:Xpa protein, mouse