Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition.
Mice that are genetically engineered are becoming increasingly more powerful tools for understanding the molecular pathology of many human hereditary diseases, especially those that confer an increased predisposition to cancer. We have generated mouse strains defective in the Xpc gene, which is required for nucleotide excision repair (NER) of DNA. Homozygous mutant mice are highly prone to skin cancer following exposure to UVB radiation, and to liver and lung cancer following exposure to the chemical carcinogen acetylaminofluorene (AAF). Skin cancer predisposition is significantly augmented when mice are additionally defective in Trp53 (p53) gene function. We also present the results of studies with mice that are heterozygous mutant in the Apex (Hap1, Ref-1) gene required for base excision repair and with mice that are defective in the mismatch repair gene Msh2. Double and triple mutant mice mutated in multiple DNA repair genes have revealed several interesting overlapping roles of DNA repair pathways in the prevention of mutation and cancer.
Friedberg
E C
EC
Laboratory of Molecular Pathology, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. friedberg.erro1@pathology.swmed.edu
Bond
J P
JP
Burns
D K
DK
Cheo
D L
DL
Greenblatt
M S
MS
Meira
L B
LB
Nahari
D
D
Reis
A M
AM
D000818:Animals; D019757:Carbon-Oxygen Lyases / Q000235:genetics; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D009369:Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C501002:Xpc protein, mouse; C086984:XPC protein, human; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase