Preventing DNA over-replication: a Cdk perspective

Abstract

The cell cycle is tightly controlled to ensure that replication origins fire only once per cycle and that consecutive S-phases are separated by mitosis. When controls fail, DNA over-replication ensues: individual origins fire more than once per S-phase (re-replication) or consecutive S-phases occur without intervening mitoses (endoreduplication). In yeast the cell cycle is controlled by a single cyclin dependent kinase (Cdk) that prevents origin licensing at times when it promotes origin firing, and that is inactivated, via proteolysis of its partner cyclin, as cells undergo mitosis. A quantitative model describes three levels of Cdk activity: low activity allows licensing, intermediate activity allows firing but prevents licensing, and high activity promotes mitosis. In higher eukaryotes the situation is complicated by the existence of additional proteins (geminin, Cul4-Ddb1 Cdt2 , and Emi1) that control licensing. A current challenge is to understand how these various control mechanisms are co-ordinated and why the degree of redundancy between them is so variable. Here the experimental induction of DNA over-replication is reviewed in the context of the quantitative model of Cdk action. Endoreduplication is viewed as a consequence of procedures that cause Cdk activity to fall below the threshold required to prevent licensing, and re-replication as the result of procedures that increase that threshold value. This may help to explain why over-replication does not necessarily require reduced Cdk activity and how different mechanisms conspire to prevent over-replication. Further work is nevertheless required to determine exactly how losing just one licensing control mechanism often causes over-replication, and why this varies between cell systems.

Cyclin A–Cdk1 regulates the origin firing program in mammalian cells

“…A quantitative model has proposed for explain the biphasic effects of Cdks (28). In addition to a quantitative model, the accessibility of Cdk to substrates could play a role in the regulation of the S-phase program.…”

CDKB1;1 Forms a Functional Complex with CYCA2;3 to Suppress Endocycle Onset

“…Generally, CDKs fulfill three major roles during mitotic cell cycle progression: entry into S phase, promotion of mitosis, and prevention of DNA rereplication (Porter, 2008). In fission yeast (Schizosaccharomyces pombe), the mitotic CDK complex hinders relicensing of replicated DNA by its association with the replication complex during chromosome duplication and prevents reinitiation of DNA synthesis (Wuarin et al, 2002).…”

“…In yeast that has only one single CDK to control the cell cycle, a quantitative model describes three levels of CDK activity: low, which allows licensing of DNA replication; intermediate, which initiates DNA replication but prevents relicensing; and high, which enables mitosis (Stern and Nurse, 1996;Porter, 2008). Although cell cycle regulation is more complex in higher eukaryotes, a quantitative model for CDK action is still partially applicable (Krasinska et al, 2008;Porter, 2008). From this point of view, an intermediate CDKB1;1 activity during the S phase could be a working mechanism that represses relicensing.…”

Loss of anchorage in checkpoint-deficient cells increases genomic instability and promotes oncogenic transformation

“…On the other hand, our results clearly demonstrate how p27 induction, by inhibiting cyclin-CDK activity in checkpoint-deficient cells, whilst protecting against immediate outgrowth (and thus still acting to protect against cancer) does so imperfectly, resulting in an increase in genomic instability, which increases the rate of oncogenic transformation as a result of further genetic changes (examples of which could be p27 loss or Ras activation). This might be partly explained by the fact that CDK activity can prevent rereplication (Porter, 2008), which, combined with loss of cell-cycle checkpoints, might be expected to promote genomic instability (Srinivasan et al, 2007;Vaziri et al, 2003).…”

“…Moreover, we made similar findings in a human cell model of oncogenic transformation. Chromosomal instability is a well-known hallmark of many cancer cells, and might contribute to the initiation and progression of tumours (Rajagopalan and Lengauer, 2004). Here, we describe a new link between loss of anchorage, the development of chromosomal instability and cellular transformation.…”