Functional screen of human MCM2-7 variant alleles for disease-causing potential

Nathan A. Steere, Satoru Yamaguchi, Catherine A. Andrews, Ivan Liachko, Tomoka Nakamura, Naoko Shima

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Origin licensing builds a fundamental basis for genome stability in DNA replication. Recent studies reported that deregulation of origin licensing is associated with replication stress in precancerous lesions. The heterohexameric complex of minichromosome maintenance proteins (MCM2-7 complex) plays an essential role in origin licensing. Previously, we reported the recovery of the first viable Mcm mutant allele (named Mcm4Chaos3) in mice. The Mcm4Chaos3 allele destabilizes the MCM2-7 complex, leading to chromosome instability and the formation of spontaneous tumors in Mcm4Chaos3 homozygous mice. Supporting our finding, a recent study reported that mice with reduced expression of MCM2 die with lymphomas within the first few months after birth. These data strongly suggest that mutant Mcm2-7 genes are cancer-causing genes with nearly complete penetrance in mice. This could be the case for humans as well. Nevertheless, related investigations have not been undertaken due to the essential nature of the MCM2-7 genes. To circumvent this problem, we focused on the variant alleles of human MCM2-7 genes derived from single nucleotide polymorphisms. We created a total of 14 variant alleles in the corresponding genes in Saccharomyces cerevisiae. The phenotypic consequence was assayed for minichromosome loss, a surrogate phenotype for genome instability and cancer susceptibility. This screen identified a MCM5 variant allele with pathogenic potential. This allele deserves further investigations on its effect on cancer development in human populations.

Original languageEnglish (US)
Pages (from-to)74-78
Number of pages5
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume666
Issue number1-2
DOIs
StatePublished - Jun 18 2009

Keywords

  • Carcinogenesis
  • Genome stability
  • MCM2-7 genes
  • Origin licensing
  • Variant alleles

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