In eukaryotic cells, including human cells, the replication of the DNA genome occurs only at a specified time during the mitotic life cycle of the cell. This period is referred to as the Synthetic or S phase. S phase is temporally separated from the Mitotic, or M phase (where duplicated chromosomes distribute equally to both daughter cells), and by two non-DNA synthetic periods referred to as gap 1 (G1 ) and gap 2 (G2 ) phases, which occur before and after the S phase, respectively (Figure 1). Among other things, the cell prepares for DNA synthesis in G1 , and for mitosis in G2 . The cell regulates DNA synthesis by allowing it to occur only once per cell cycle, and only during S phase, in cells preparing to divide by a mitotic process.

Fig1. Progress through the mammalian cell cycle is continuously monitored via multiple cell-cycle checkpoints. DNA, chromosome, and chromosome segregation integrity are continuously monitored throughout the cell cycle. If DNA damage is detected in either the G1 or the G2 phase of the cell cycle, if the genome is incompletely replicated, or if normal chromosome segregation machinery is incomplete (ie, a defective spindle), cells will not progress through the phase of the cycle in which defects are detected. In some cases, if the damage cannot be repaired, such cells undergo programmed cell death (apoptosis). Note that cells can reversibly leave the cell cycle during G1 entering a nonreplicative state termedG0. When appropriate signals/conditions occur, cells reenter G1 and progress normally through the cell cycle as depicted.

All eukaryotic cells have gene products that govern the transition from one phase of the cell cycle to another. The cyclins are a family of proteins whose intracellular concentrations cyclically increase and decrease at specific times during the cell cycle—thus their name. The cyclins activate, at the appropriate time, different cyclin-dependent protein kinases (CDKs) that phosphorylate substrates essential for progression through the cell cycle (Figure 2). For example, cyclin D levels rise in late G1 phase and allow progression beyond the start (yeast) or restriction point (mammals), the point beyond which cells irrevocably proceed into the S or DNA synthesis phase.

Fig2. Schematic illustration of the points during the mammalian cell cycle during which the indicated cyclins and cyclin-dependent kinases are activated. The thickness of the various colored lines is indicative of the extent of activity.

The D cyclins activate CDK4 and CDK6. These two kinases are also synthesized during G1 in cells undergoing active division. The D cyclins and CDK4 and CDK6 are nuclear proteins that assemble as a complex in late G1 phase. The cyclin–CDK complex is now an active serine–threonine protein kinase. One substrate for this kinase is the retinoblastoma (Rb) protein. Rb is a cell-cycle regulator because it binds to and inactivates a transcription factor (E2F) necessary for the transcription of certain genes (histone genes, DNA replication proteins, etc.) needed for progression from G1 to S phase. The phosphorylation of Rb by CDK4 or CDK6 results in the release of E2F from Rb-mediated transcription repression—thus, gene transcription activation ensues and cell-cycle progression takes place.

Other cyclins and CDKs are involved in different aspects of cell-cycle progression (Table 1). Cyclin E and CDK2 form a complex in late G1 . Cyclin E is rapidly degraded, and the released CDK2 then forms a complex with cyclin A. This sequence is necessary for the initiation of DNA synthesis in S phase. A complex between cyclin B and CDK1 is rate-limiting for the G2 /M transition in eukaryotic cells.

Table1. Cyclins and Cyclin-Dependent Kinases Involved in Cell-Cycle Progression

Many of the cancer-causing viruses (oncoviruses) and cancer inducing genes (oncogenes) are capable of alleviating or disrupting the restriction that normally controls the entry of mammalian cells from G1 into the S phase. From the foregoing, one might have surmised that excessive production of a cyclin, loss of a specific CDK inhibitor, or production or activation of a cyclin/CDK at an inappropriate time might result in abnormal or unrestrained cell division. Similarly, the oncoproteins (or transforming proteins) produced by several DNA viruses target the Rb transcription repressor for inactivation, inducing cell division inappropriately, while inactivation of Rb, itself a tumor suppressor gene, leads to uncontrolled cell growth and tumor formation.

During the S phase, mammalian cells contain greater quantities of DNA polymerase than during the nonsynthetic phases of the cell cycle. Furthermore, those enzymes responsible for formation of the substrates for DNA synthesis—that is, deoxyribonucleoside triphosphates—are also increased in activity, and their expression drops following the synthetic phase until the reappearance of the signal for renewed DNA synthesis. During the S phase, the nuclear DNA is completely replicated once and only once. After chromatin has been replicated, it is marked so as to prevent its further replication until it again passes through mitosis. This process is termed replication licensing. The molecular mechanisms for this phenomenon in human cells involve dissociation and/or cyclin–CDK phosphorylation and subsequent degradation of several origin binding proteins that play critical roles in replication complex formation. Consequently, origins fire only once per cell cycle.

In general, a given pair of chromosomes will replicate simultaneously and within a fixed portion of the S phase on every replication. On a chromosome, clusters of replication units replicate coordinately. The nature of the signals that regulate DNA synthesis at these levels is unknown, but the regulation does appear to be an intrinsic property of each individual chromosome that is mediated by the several replication ori gins contained therein.

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مواضيع ذات صلة

Formation of Replication Bubbles

Initiation & Elongation of DNA Synthesis

The Exact Function of Much of the Mammalian Genome is Not Well Understood

DNA is organized into Chromosomes

Some Regions of Chromatin are “Active” & Others are “Inactive”

The Nucleosome Contains Histone & DNA

Histones Are the Most Abundant Chromatin Proteins

Specific Nucleases Digest Nucleic Acids

Directions for Future Research in Molecular Biology

The ras-fos-jun Pathway

Recessive Oncogenic Mutations, Tumor Suppressors

Small RNA