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Review
. 2008 Jul 1;7(7):1180-9.
doi: 10.1016/j.dnarep.2007.12.006. Epub 2008 Feb 12.

Nucleotide excision repair deficient mouse models and neurological disease

Laura J Niedernhofer  1
Affiliations
Review

Nucleotide excision repair deficient mouse models and neurological disease

Laura J Niedernhofer. DNA Repair (Amst). .

Abstract

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA base damage. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human diseases caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated aging. All three syndromes include neurological disease, indicating an important role for NER in protecting against spontaneous DNA damage as well. To study the pathophysiology caused by DNA damage, numerous mouse models of NER-deficiency were generated by knocking-out genes required for NER or knocking-in disease-causing human mutations. This review explores the utility of these mouse models to study neurological disease caused by NER-deficiency.

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Figures

Figure 1
Figure 1. Schematic diagram of nucleotide excision repair highlighting mutant mouse strains available
Two subpathways of NER are delineated based on the location of a DNA lesion in the genome and how the damage is recognized. XPC-HR23B binds helix-distorting lesions throughout the genome in global genome-NER (GG-NER). This is facilitated by the DDB complex (DDB1 and XPE/DDB2) specifically in the case of damage caused by UV-irradiation. DDB is part of the Cul4A complex, which ubiquitylates XPC leading to stable association of this protein to damaged DNA. Lesions on the transcribed strand of genes can block RNA polymerase II-mediated transcription, leading to activation of transcription-coupled NER (TC-NER). Either XPC in GG-NER or CSA and CSB in TC-NER recruit the multi-subunit transcription factor TFIIH to the site of damage (subunits indicated with dots). XPG is required to stabilize TFIIH. The XPB and XPD subunits of TFIIH are helicases that unwind the DNA around the lesion. XPA and RPA then bind and stabilize the open structure and recruit ERCC1-XPF. This nuclease incises the damaged strand of DNA 5′ to the lesion. XPG makes the 3′ incision. The lesion is removed in a single-stranded oligonucleotide, leaving behind a gap that is filled by the replication machinery (polymerase δ and ε, PCNA, RPA and RFC). The DNA backbone is sealed by DNA ligase I. Colored circles indicate gene products that have been targeted in the mouse. -/- indicates mutant strains where the protein of interest is undetectable. Homozygous deletion of Ddb1, Xab2, Xpb or Xpd is incompatible with life. Thus Ddb1 was conditionally knocked out (F/F = floxed allele) and point mutations in Xpd causing TTD or CS were knocked into the mouse genome (m/m).
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