A reduction of licensed origins reveals strain-specific replication dynamics in mice.
Replication origin licensing builds a fundamental basis for DNA replication in all eukaryotes. This occurs during the late M to early G1 phases in which chromatin is licensed by loading of the MCM2-7 complex, an essential component of the replicative helicase. In the following S phase, only a minor fraction ... of chromatin-bound MCM2-7 complexes are activated to unwind the DNA. Therefore, it is proposed that the vast majority of MCM2-7 complexes license dormant origins that can be used as backups. Consistent with this idea, it has been repeatedly demonstrated that a reduction (~60%) in chromatin-bound MCM2-7 complexes has little effect on the density of active origins. In this study, however, we describe the first exception to this observation. A reduction of licensed origins due to Mcm4 ( chaos3 ) homozygosity reduces active origin density in primary embryonic fibroblasts (MEFs) in a C57BL/6J (B6) background. We found that this is associated with an intrinsically lower level of active origins in this background compared to others. B6 Mcm4 ( chaos3/chaos3 ) cells proliferate slowly due to p53-dependent upregulation of p21. In fact, the development of B6 Mcm4 ( chaos3/chaos3 ) mice is impaired and a significant fraction of them die at birth. While inactivation of p53 restores proliferation in B6 Mcm4 ( chaos3/chaos3 ) MEFs, it paradoxically does not rescue animal lethality. These findings indicate that a reduction of licensed origins may cause a more profound effect on cell types with lower densities of active origins. Moreover, p53 is required for the development of mice that suffer from intrinsic replication stress.
Mesh Terms:
Animals, Cell Proliferation, Cell Transformation, Neoplastic, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA Helicases, DNA Replication, Fetal Viability, Gene Expression Regulation, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Proliferating Cell Nuclear Antigen, Rad51 Recombinase, Replication Origin, Species Specificity, Transcription, Genetic, Tumor Suppressor Protein p53, Up-Regulation
Animals, Cell Proliferation, Cell Transformation, Neoplastic, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, DNA Helicases, DNA Replication, Fetal Viability, Gene Expression Regulation, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Transgenic, Proliferating Cell Nuclear Antigen, Rad51 Recombinase, Replication Origin, Species Specificity, Transcription, Genetic, Tumor Suppressor Protein p53, Up-Regulation
Mamm. Genome
Date: Oct. 01, 2011
PubMed ID: 21611832
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