Reduced Mcm2 Expression Results in Severe Stem/Progenitor Cell Deficiency and Cancer

¹ Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York, 14263, USA

^* To whom correspondence should be addressed. E-mail: steven.pruitt{at}roswellpark.org.

	Abstract

Mcm2 is a component of the DNA replication licensing complex which marks DNA replication origins during G1 of the cell cycle for use in the subsequent S-phase. It is expressed in stem/progenitor cells in a variety of regenerative tissues in mammals. Here, we have utilized the Mcm2 gene to develop a transgenic mouse in which somatic stem/progenitor cells can be genetically modified in the adult. In these mice a tamoxifen inducible form of Cre-recombinase is integrated 3' to the Mcm2 coding sequence and expressed via an internal ribosome entry site (IRES). Heterozygous Mcm2^{IRES-CreERT2/wt} mice are phenotypically indistinguishable from wild type at least through one year of age. In bigenic Mcm2^{IRES-CreERT2/wt}; Z/EG reporter mice, tamoxifen dependent EGFP expression is inducible in a wide variety of somatic stem cells and their progeny. However, in Mcm2^{IRES-CreERT2/IRES-CreERT2} homozygous embryos or MEFs, Mcm2 is reduced to approximately a third of wild type levels. Despite the fact that these mice develop normally and are asymptomatic as young adults, lifespan is greatly reduced with most surviving to only 10-12 weeks of age. They demonstrate severe deficiencies in the proliferative cell compartments of a variety of tissues, including the sub-ventricular zone of the brain, muscle, and intestinal crypts. However the immediate cause of death in most of these animals is cancer where the majority develop lymphomas. These studies directly demonstrate that deficiencies in the function of the core DNA replication machinery which are compatible with development and survival nonetheless result in a chronic phenotype leading to stem cell deficiency in multiple tissues and cancer.

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				A. Ibarra, E. Schwob, and J. Mendez Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication PNAS, July 1, 2008; 105(26): 8956 - 8961. [Abstract] [Full Text] [PDF]