Abstract
The minichromosome maintenance (MCM) complex is a replicative helicase, which is essential for chromosome DNA replication. In recent years, the identification of a novel MCM-binding protein (MCM-BP) in most eukaryotes has led to numerous studies investigating its function and its relationship to the MCM complex. However, the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood; in addition, the functional role of MCM-BP remains controversial and may vary between model organisms. The present study aims to elucidate the nature and biological function of the MCM-BP ortholog, Mcb1, in fission yeast. The Mcb1 protein continuously interacts with MCM proteins during the cell cycle in vivo and can interact with any individual MCM subunit in vitro. To understand the detailed characteristics of mcb1(+), two temperature-sensitive mcb1 gene mutants (mcb1(ts)) were isolated. Extensive genetic analysis showed that the mcb1(ts) mutants were suppressed by a mcm5(+) multicopy plasmid and displayed synthetic defects with many S-phase-related gene mutants. Moreover, cyclin-dependent kinase modulation by Cig2 repression or Rum1 overproduction suppressed the mcb1(ts) mutants, suggesting the involvement of Mcb1 in pre-RC formation during DNA replication. These data are consistent with the observation that Mcm7 loading onto replication origins is reduced and S-phase progression is delayed in mcb1(ts) mutants. Furthermore, the mcb1(ts) mutation led to the redistribution of MCM subunits to the cytoplasm, and this redistribution was dependent on an active nuclear export system. These results strongly suggest that Mcb1 promotes efficient pre-RC formation during DNA replication by regulating the MCM complex.
Highlights
minichromosome maintenance (MCM)-BP is a novel binding partner of the MCM complex; the mechanisms by which MCM-binding protein (MCM-BP) functions and associates with MCM complexes are not well understood
Immunoprecipitation and/or mass spectrometry studies in humans, Xenopus, and fission yeast showed that MCM-BPs interact with all MCM complex subunits, except Mcm2 [26, 27, 29, 30]
The functions of MCM-BP during DNA replication have been extensively studied in several organisms; the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood, and there seems to be no unified view concerning the shared common function of MCM-BP across species
Summary
MCM-BP is a novel binding partner of the MCM complex; the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. The fission yeast Mcb is widely distributed in the cytoplasm and nucleoplasm and is bound to chromatin [29]; Xenopus MCM-BP is imported into the nucleus just before the dissociation of Mcm from chromatin near the end of S-phase These differences in the localization of MCM-BP may affect other functions associated with the MCM complex proteins. The functions of MCM-BP in DNA replication have been extensively studied; the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood, and the functional role of MCM-BP is controversial and may vary among model organisms To address these remaining questions, the functional roles of MCM-BP were examined by genetic analysis of temperaturesensitive mutants in fission yeast. Sion,” we shall discuss the role of MCM-BP in regulating MCM function(s) during DNA replication in the context of these results
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