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-fo ld increased incidence of skin cancer. The ERCC1 protein is essential for N ER, but ERCC1 knockout mice are not a model for XP, In the absence of exoge nous DNA-damaging agents, these mice are runted and die before weaning, wit h dramatically accelerated liver polyploidy and elevated levels of p53, Her e we present a morphological, immunological, and molecular study to underst and 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 re duced. 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 rescue d by p53 deficiency, but we show that p53 is responsible for the reduced DN A replication and binucleation. We consider that the liver phenotype is a r esponse to unrepaired endogenous DNA damage, which may reflect an additiona l non-NER-related function for the ERCC1 protein.-Nunez, F,, Chipchase, M. D., Clarke, A. R., Melton, D. W. Nucleotide excision repair gene (ERCC1) de ficiency causes G(2) arrest in hepatocytes and a reduction in liver binucle ation: the role of p53 and p21.