title: A reduction of licensed origins reveals strain-specific replication dynamics in mice.
abstract: 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.
authors: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA. shima023@umn.edu
authors: Tsuyoshi
authors: T
authors: Kawabata
authors: Satoru
authors: S
authors: Yamaguchi
authors: Tavanna
authors: T
authors: Buske
authors: Spencer W
authors: SW
authors: Luebben
authors: Marsha
authors: M
authors: Wallace
authors: Ilze
authors: I
authors: Matise
authors: John C
authors: JC
authors: Schimenti
authors: Naoko
authors: N
authors: Shima
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