DNA replication and damage checkpoints and meiotic cell cycle controls in the fission and budding yeasts

Abstract

The cell cycle checkpoint mechanisms ensure the order of cell cycle events to preserve genomic integrity. Among these, the DNA-replication and DNA-damage checkpoints prevent chromosome segregation when DNA replication is inhibited or DNA is damaged. Recent studies have identified an outline of the regulatory networks for both of these controls, which apparently operate in all eukaryotes. In addition, it appears that these checkpoints have two arrest points, one is just before entry into mitosis and the other is prior to chromosome separation. The former point requires the central cell-cycle regulator Cdc2 kinase, whereas the latter involves several key regulators and substrates of the ubiquitin ligase called the anaphase promoting complex. Linkages between these cell-cycle regulators and several key INTRODUCTIONIn eukaryotes the cell cycle is divided into two phases, interphase and mitosis [1]. Interphase consists of G1, S and G2 phases. Mitosis can be sub-divided into prophase, metaphase, anaphase and telophase. Chromosomes condense during prophase, align during metaphase, separate during anaphase and decondense during telophase. There are several control points during the cell cycle : in late G1, called Start in yeast or the Restriction point in mammals, in late G2 and just prior to anaphase. To pass each point, cells have to fulfil several prerequisites. Before passing Start, cells can undergo two developmental programmes, i.e. entry into the mitotic cell cycle or sexual development. Adequate nutritional conditions and a critical cell size are required to traverse Start. During G2, cells have to check whether DNA replication is completed and ensure that DNA is not damaged. Before chromosome separation cells also examine whether chromosomes are aligned and spindles are formed properly. These cell-cycle checkpoints are the mechanisms that govern the order of the cell-cycle events, because if the order of the events is incorrect then a full complement of genetic information is not transmitted at cell division, which may lead to cancer in higher eukaryotes.Much is now known about regulation of the eukaryotic cell cycle but two areas have yet to be fully understood. The first area is concerned with the molecular mechanisms acting during the DNA-replication and DNA-damage checkpoints, which block mitosis if DNA replication is incomplete or DNA is damaged. The second concerns the controls which operate during the meiotic cell cycle. In recent years, some progress has been made in both of these areas and the purpose of the present review is to Abbreviations used : APC, anaphase-promoting complex ; Cln, G1 cyclin ; FHA, forkhead associated ; PCNA, proliferating-cell nuclear antigen ; SPB, spindle-pole body ; CDK, cyclin-dependent kinase ; RFC, replication factor C ; MCM, minichromosome maintenance ; ORC, origin-recognition complex.1 To whom correspondence should be addressed (e-mail murakami!icrf.icnet.uk). REGULATION OF MITOTIC CELL CYCLE BY CYCLIN-DEPENDENT KINASE (CDK) IN FISSION YEASTThere are a number of protein...

A checkpoint control linking meiotic S phase and recombination initiation in fission yeast

“…This discrepancy might be due to the different roles of the checkpoint proteins in the two yeasts. Budding yeast Mec1 is essential for viability, whereas fission yeast Rad3p is not (11,24). The hypomorphic mutant mec1-1 is deficient only in coupling of DNA replication and meiotic nuclear division, the link between DNA replication and DSB formation being intact (23).…”

“…The proteins Rad1p, Rad3p, Rad9p, Rad17p, Rad26p, Hus1p, and Cds1p are required for operation of the DNA-replication checkpoint in fission yeast (9)(10)(11)13). The DNA-replicationcheckpoint proteins send a signal to block mitosis via the cyclin-dependent kinase Cdc2p complexed with the B-type cyclin Cdc13p (9).…”

“…The DNA-replication checkpoint operates during both the mitotic cell cycle and meiosis to ensure that chromosome segregation is blocked if DNA replication is incomplete (9)(10)(11)(12). The proteins Rad1p, Rad3p, Rad9p, Rad17p, Rad26p, Hus1p, and Cds1p are required for operation of the DNA-replication checkpoint in fission yeast (9)(10)(11)13).…”

DNA Replication Checkpoint Control Mediated by the Spindle Checkpoint Protein Mad2p in Fission Yeast

“…In fission yeast, like other eukaryotes, the spindle checkpoint therefore functions only after DNA replication is complete. In fission yeast two checkpoint kinases, Rad3p and Cds1p, are important for the DNA replication checkpoint (1)(2)(3). The spindle checkpoint requires the interaction of Mad2p with the anaphase-promoting complex (APC) 1 (7,8).…”

“…Cell cycle checkpoints monitor cell cycle progression to ensure the integrity of the genome and the fidelity of sister chromatid separation (1)(2)(3). The DNA replication checkpoint blocks entry into mitosis if DNA replication is incomplete, whereas the spindle checkpoint delays sister chromatid separation until each and every kinetochore has achieved a bipolar attachment to the mitotic spindle apparatus.…”