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MOUSE MODELS TO STUDY THE CONSEQUENCES OF DEFECTIVE
NUCLEOTIDE EXCISION REPAIR.
JAN DE BOER AND JAN H.J. HOEIJMAKERS
IvIGC-Depf. o/Cell Biology and Genetics, Erasmus University, P.G. Bo:r 17383000 DR,
Rotterdam, The Netherlands.
Combined biochemical, genetical and cell biological progress in the past decades has
culminated in a breakthrough in the insight into the molecular mechanism of nucleotide
excision rcpair (NER). This in turn has provided clues to understanding the molecular basis
of the clinical heterogeneity observed in patients with a defect in NER. [n recent years,
mouse models have been established for the different human NER syndromes. Conventional
knockout gene targeting of the mouse XPA gene yielded a model for the prototype DNA
repair syndrome xeroderma pigmentosurn (XP) with a complete NER defect [1,2]. Similarly,
by targeting the XPC gene, associated with a specific deficiency in the global genome repair
(GGR) pathway [3,4], a valid model for the group C form of thc disease was gencratcd. A
mousc model for Coekayne syndrome (CS), with a selective impainnent of transcriptioncoupled
repair (TCR) was obtained by mimicking a truncating CSB null allele found in a CS
group B patient [5]. Recently, a mutant with a partial repair defect and associated remarkable
clinical symptoms oftrichothiodystrophy (TTD) was established in the mouse by mimicking
a point mutation identified in the XPD gene of a photosensitive TTD patient [G]. Besides
mouse mutants with specific NER defects, knockouts and more subtle mutants have been
generated for NER proteins that are involved simultaneously in other cellular processes as
basal transcription (XPD and XPB [7 and G. Weeda, manuscript in prep.]), mitotic
recombination and cross-link repair (ERCCl [8, 9]) and ubiquitination (mHR23A and B, 1.
Ng, K, Sugasawa and B. van del" Horst, pers. comm.). The generation of this series of mouse
mutants allows ill vivo investigation of some intriguing questions that have puzzled the field,
SLlch as the paradoxical absence of cancer development in TTD and CS despite their NER
deficiencies, the pathophysiology ofthc non-NER related clinical symptoms in TTD and CS
paticnts and the proposed involvement ofNER and transcription in the process of aging. This
review will focus on data obtained thusfar with established NER mousc models and discllss
further utilization of thc mousc mutants for unraveling some of the fascinating and mcdically
relevant aspects associated with dcfects in NER and related processes.
Biochimie, in press