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Cell Research (1999), 9, 163-170

Regulation of eukaryotic DNA replication and nuclear structure

Shanghai Institute of Biochemistry, Chinese Academy of Sciences,Shanghai 200031, China e-mail:

In eukaryote, nuclear structure is a key component for the functions of eukaryotic cells. More and more evidences show that the nuclearstructure plays important role in regulating DNA replication. The nuclear structure provides a physical barrier for the replication licensing, participates in the decision where DNA replication initiates, and organizes replication proteins as replication factory for DNA replication. Through these works, new concepts on the regulation of DNA replication have emerged, which will be discussed in thisminireview. Key words: DNA replication, nuclear structure, replication licensing, replication origin, replication factory

Regulatory mechanisms for DNA replication are central to the control of the cell-cycle in eukaryotic cells. Recently, considerable progress has been made in our understanding of the relationship between regulation of eukaryotic DNA replication and nuclear structure. Thisreview will briefly outline the progress and discuss some new concepts appearing from the studies.

Licensing of DNA replication: the initiation-competent state
Replication of the eukaryotic genome occurs only once during the S-phase of each cell cycle. More than 20 years ago, Rao and Johnson found that DNA synthesis in G1 nuclei was induced by fusing G1-phase human cells with S-phase human cells,but no DNA synthesis in G2 nuclei was detected by fusing G2-phase cells with S-phase cells.

Regulation of eukaryotic DNA replication and nuclear structure Thus, G1-phase cells but not G2-phase cells are in a replication-competent state[1]. Lately, Laskey and Blow revealed that if the G2-phase nuclear membrane was permeabilized artificially, nuclei became competent for a second round of DNAsynthesis[2]. They proposed a model that an essential replication factor (replication licensing factor), which allows the initiation of DNA replication to occur, can only access chromatin during mitosis after nuclear membrane breakdown. Then the factor would be inactivated during DNA replication to ensure only one round of DNA synthesis per cell-cycle[1],[2]. With a genetic screening assay in yeast, afamily of physically and genetically interacting proteins have been suggested to be the putative replication licensing factor, including the MCM2, MCM3 and CDC46/MCM5 proteins from Sccharomyces cerevisiae, and NDA1, NDA4 and CDC21 from Schizosaccaromyces pombe[3],[4]. MCM proteins are essential for minichromosome maintenance in S. cerevisiae, and appear in the nucleus at the end of mitosis,remain during G1 and then disappear from the nucleus at the beginning of S phase. By using biochemical assays, three laboratories subsequently reported the identification of components of the licensing factors in higher eukaryotic cells, Xenopus homologues of the yeast MCM protein family ([5] and references therein). In addition, a number of mammalian homologues of the MCM protein family were alsoidentified, such as the human CDC21, CDC46, CDC47 and P1/MCM3[6],[7], and murine P1 protein[8]. Interestingly, most of the homologues of the MCM protein family, such as S. pombe CDC21, Xenopus MCM3, CDC21, and human CDC21, CDC46, CDC47 and P1/MCM3, have been found to be located in the nucleus throughout the cell cycle[6-11]. This phenomenon is not consistent with the licensing factor model, in whichthe licensing factor should disappear from the nucleus after the progression of S phase. Two kinds of explanation for this discrepancy have been proposed. First, regulation of nuclear import of MCM homologues may not be an essential aspect of licensing function[11]. This suggestion is supported by the observation that two populations of MCM homologues exist in the amphibian and mammalian nucleus,...