ABSTRACT
CSB Mutant MiceCSB m utant mice were created w ith a homozygous m utation (K337stop) which mimics the m utant allele in hum an CS-B patient (CS1AN) and encodes a truncated CSB protein8 (Table 2). Csb'1' mice exhibit all the N E R characteristics o f hum an CS patients: U V sensitivity, inactivation o f T C -N E R , unaffected G G -N ER and inability to resume RNA synthesis after U V exposure. However, other CS features such as postnatal growth failure and neurological dysfunction are present in m ild form. After 6 m onths o f age a significant num ber o f C s b mice start to develop a stereotypic hyperactive behavior known as circling or waltzing, suggestive o f the development o f deafness.8 Spontaneous loss o f retinal photoreceptor cells w ith age was also observed in the Csb~h mouse.9 Unlike CS humans, Csb~h mice are prone to UVB-induced skin cancer.8 However, these m utant mice are no t abnormally prone to tum ors caused by oral administration o f benzo[^] pyrene.10The basal (steady-state) levels o f oxidative D N A damage, in cells from Csb~/_ mice, are no t different from those in wild-type mice and do no t increase with age.11 C s b 'mice, that are also homozygous defective for O ggl (a D N A glycosylase involved in base excision repair o f oxidative D N A lesions), have also been created.11'13 Com pared to O g g l'1', Csb~l~ O g g l mice accumulate with age several fold higher levels o f oxidated purine modifications in hepatocytes, spleenocytes and kidney cells. The repair o f oxidative D N A lesions is only slighdy affected in Csb~l~ cells, more compromised in Oggl~'~ cells, bu t virtually absent in Csb~l~ Oggl~l~ cells.11 Despite the deficiency in repair o f oxidative D N A damage, C sb " O g g l'1' mice show essentially the same phenotype as Csb~'~ mice.12Severe developmental abnormalities, similar to the hum an CS phenotype are observed in Csb"/_ mice, that are also homozygously deficient for XPA, which is essential for both G G -N ER and T C -N E R ,14,15 or X P C which is only required for G G -N ER but n o t for T C -N E R .12,15
Although clinical differences between hum an CS-A and CS-B have no t yet been found, cells from Csa~'~ and Csb~h mice show different responses to oxidative D N A damage.16 Embryonic fibroblasts from C sb~/_ mice, but no t C sa"/_ mice, are hypersensitive to y radiation and to paraquat, known to generate reactive oxygen species in cells. W hen fed with food containing di(2-ethylhexyl) phthalate, which promotes oxidative D N A damage in the liver, C sb~f~ mice, but no t Csa~h mice, lose weight. However, both C sa~/_ and C s b embryonic stem cells are slightly sensitive to ionizing radiation.16 Furthermore, when they were exposed to ionizing radiation, both Csb~l_ and
X p c fw cs mutan t mice, which bear a homozygous G602D mutation and mimicking a X P-D /CS patient (XPCS2), were created recently17 (Table 2). Primary embryonic fibroblasts from X pd!® ^ mice have no detectable RRS, indicating an absolute lack o f T C -N E R activity. Analogous to human X P -D /C S cells, X p d f PCS cells retained — 30% U D S activity and are hypersensitive to U V irradiation.17 Spontaneously immortalized embryonic fibroblasts from X p c f^ ^ mice are moderately sensitive to y irradiation and show a defect in reactivation o f a reporter plasmid containing oxidative D N A damage, consistent with a deficiency in repair ability o f D N A damaged oxidatively.17 X p d f p c s mice are even more predisposed to U V induced skin cancer than those entirely NER-deficient (e.g.,Xp^_/"). H um an X P -D /C S cells are able to incise their D N A as efficiently as normal cells following U V exposure.18 These incisions are, however, uncoupled from the rest o f the N ER process, resulting in accumulation o f uncontrolled D N A breakage.18 Similar to human X P -D /C S cells, X p d f PCS mouse cells appear to have an increased num ber o f U V induced D N A incisions that are no t coupled to the rest o f the N ER process.17 The unique UV-induced skin cancer predisposition in X p d f ^ mice may be caused by the failure to remove U V lesions and by the uncoupling o f the incision event from the rest o f the N E R process.17The mean lifespan ofX p c f® ^ mice (546 days; SE = 22.7) is significantly (-15% ) shorter than that o f control mice (641 days; SE = 43.3).17 Further reduction o f D N A repair capacity in X p d ^ ^ mice by concom itant inactivation of.X p a t severely exacerbates CS features. X p t f ^ c s X paT 1-double m utant mice are born normally but display enhanced progressive postnatal growth failure, neurodysfunction and death within 3 weeks.17
