Nucleotide excision repair gene (ERCC1) deficiency causes G(2) arrest in hepatocytes and a reduction in liver binucleation: the role of p53 and p21.
A wide range of DNA lesions, both UV and chemically induced, are dealt with by the nucleotide excision repair (NER) pathway. Defects in NER result in human syndromes such as xeroderma pigmentosum (XP), where there is a 1000-fold increased incidence of skin cancer. The ERCC1 protein is essential for NER, but ERCC1 knockout mice are not a model for XP. In the absence of exogenous DNA-damaging agents, these mice are runted and die before weaning, with dramatically accelerated liver polyploidy and elevated levels of p53. Here we present a morphological, immunological, and molecular study to understand the mechanism for the unusual liver pathology in ERCC1-deficient mice. We show that the enlarged ERCC1-deficient hepatocytes are arrested in G(2) and that DNA replication and the normal process of binucleation are both reduced. This is associated with a p53-independent increase in expression of the cyclin-dependent kinase inhibitor p21. The most dramatic feature of the ERCC1-deficient liver phenotype, the accelerated polyploidy, is not rescued by p53 deficiency, but we show that p53 is responsible for the reduced DNA replication and binucleation. We consider that the liver phenotype is a response to unrepaired endogenous DNA damage, which may reflect an additional non-NER-related function for the ERCC1 protein.
Núñez
F
F
Institute of Cell and Molecular Biology, Edinburgh University, King's Buildings, Edinburgh, Scotland, U.K.
Chipchase
M D
MD
Clarke
A R
AR
Melton
D W
DW
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048429:Cell Size; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D004261:DNA Replication; D004268:DNA-Binding Proteins; D004720:Endonucleases; D016195:G2 Phase; D005838:Genotype; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010641:Phenotype; D011123:Polyploidy; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004247:DNA; D004720:Endonucleases; C499360:Ercc1 protein, mouse