49. Cockayne Syndrome-like Phenotypes in Mice Lacking the Xeroderma Pigmentosum Group G Gene

Tadahiro Shiomi, Yoshi-nobu Harada, Naoko Shiomi and Manabu Koike

Keywords: xeroderma pigmentosum, xpg, mouse model, Cockayne syndrome, growth failure

Patients suffering from xeroderma pigmentosum group G (XP-G) show complex clinical phenotypes. Some patients exhibit the signs and symptoms of both xeroderma pigmentosum and Cockayne syndrome (XP/CS). The reason for this combined phenotype is not known at present. Mutations in five genes, CSA, CSB, XPB, and XPG can cause the CS phenotype. Of these, CSA and CSB function exclusively in transcription and are required for transcription elongation and transcription coupled repair. These are not essential genes for cell survival and thus humans or mice defective in these genes can grow to an average age of 12 years or to adulthood, respectively. The XPB and XPD genes encode the subunits of the general transcription/repair factor TFIIH and hence only missense mutations in these genes are compatible with life. Apparently, some of the mutations in these genes impair transcription to a significant level to cause the XP/CS complex in a subset of XP-B and XP-D patients.

In contrast to the other four genes which have been implicated in CS, at present there is no direct evidence that XPG plays a role in transcription. A clue to a potentially vital role of XPG in survival was shown by the recent findings that XPG is required for transcription-coupled repair of oxidative DNA lesion thymine glycol by base excision repair and XPG stimulates the general genome repair of this lesion. Furthermore, it was found that missense mutations that inactivate the NER nuclease function of XPG do not affect thymine glycol repair or cause CS. Only mutations which gave rise to severely truncated XPG reduced the rate of thymine glycol repair and caused CS which is associated with growth retardation and short life span. In light of these findings, then, a likely cause of early senescence and death of xpg-deficient embryonic mouse cells and of xpg mice is the accumulation of oxidative damage including thymine glycol in the genome of the xpg mutant cells and mice. These lesions may cause the observed phenotypes by blocldng replication and transcription or by causing mutations in important regulatory genes. The fact that we did not find increased sensitivity of xpg null cells to ionizing radiation and H2O2 is not necessarily in disagreement with this reasoning. A 10-20 % reduction in the repair of thymine glycol (and other oxidative lesions such as 8-oxoG) may confer increased sensitivity that is difficult to detect in acute treatments. However, even a marginally perceptible decrease in repair of oxidative damage could lead to lethal phenotype over the long term. In this regard, we note that the XPG/CS cell lines with reduced thymine glycol repair capacity were not reported to have increased sensitivity to ionizing radiation or oxidative stress. Thus, a careful consideration of existing data on XPG mutants both in humans and in mice leads us to speculate that the premature senescence and death of xpg mice is caused by genomic instability induced by oxidative lesions which are repaired at a considerably slower rate in these mutants.

Publications:
Harada, Y., Shiomi, N., Koike, M., Ikawa, M., Okabe, M., Hirota, S., Kitamura, Y., Kitagawa, M., Matsunage, T., Nibaido, 0., Shiomi, T.: Mol. Cell. Biol., 19, 2366-2372, 1999.