DNA Synthesis Occurs During the S Phase of the Cell Cycle

In animal cells, including human cells, the replication of the DNA genome occurs only at a specified time during the life span of the cell. This period is referred to as the synthetic or S phase. This is usually temporally separated from the mitotic phase by nonsynthetic periods referred to as gap 1 (G1) and gap 2 (G2), occurring before and after the S phase, respectively (Figure 36-20). Among other things, the cell prepares for DNA synthesis in G1 and for mitosis in G2. The cell regulates its DNA synthesis grossly by allowing it to occur only at specific times and mostly in cells preparing to divide by a mitotic process.

It appears that 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 concentration increases and decreases throughout the cell cycle—thus their name. The cyclins turn on, at the appropriate time, different cyclin-dependent protein kinases (CDKs) that phosphory-late substrates essential for progression through the cell cycle (Figure 36-21). 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.

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 complex is 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 re-pression—thus, gene activation ensues and cell cycle progression takes place.

Other cyclins and CDKs are involved in different aspects of cell cycle progression (Table 36-7). 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.

Improper spindle detected

Damaged DNA detected

Damaged DNA detected

Damaged DNA detected

Incomplete replication detected

Incomplete replication detected

Damaged DNA detected

Figure 36-20. Mammalian cell cycle and cell cycle checkpoints. DNA, chromosome, and chromosome segregation integrity is 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).

Many of the cancer-causing viruses (oncoviruses) and cancer-inducing genes (oncogenes) are capable of alleviating or disrupting the apparent 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—or production at an inappropriate time—might result in abnormal or unrestrained cell division. In this context it is noteworthy that the bcl oncogene associated with B cell lymphoma appears to be the cyclin D1 gene. Similarly, the oncoproteins (or transforming proteins) pro duced by several DNA viruses target the Rb transcription repressor for inactivation, inducing cell division inappropriately.

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—ie, deoxyribonucleoside triphosphates—are also increased in activity, and their activity will diminish following the synthetic phase until the reappearance of the signal for renewed DNA

Cdk1-cyclin B Cdk1-cyclin A

Cdk2-cyclin A

Cdk1-cyclin B Cdk1-cyclin A

Cdk2-cyclin A

Cdk4-cyclin D Cdk6-cyclin D

Cdk2-cyclin E

Cdk4-cyclin D Cdk6-cyclin D

Cdk2-cyclin E

Figure 36-21. 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.

Table 36-7. Cyclins and cyclin-dependent kinases involved in cell cycle progression.

Cyclin

Kinase

Function

D

CDK4, CDK6

Progression past restriction point at G1/S boundary

E, A

CDK2

Initiation of DNA synthesis in early S phase

B

CDK1

Transition from G2 to M

synthesis. During the S phase, the nuclear DNA is completely replicated once and only once. It seems that once chromatin has been replicated, it is marked so as to prevent its further replication until it again passes through mitosis. The molecular mechanisms for this phenomenon have yet to be elucidated.

In general, a given pair of chromosomes will replicate simultaneously and within a fixed portion of the S phase upon 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.

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