Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Mar 1;5(3):a012914.
doi: 10.1101/cshperspect.a012914.

Genomic Instability in Cancer

Affiliations
Free PMC article
Review

Genomic Instability in Cancer

Tarek Abbas et al. Cold Spring Harb Perspect Biol. .
Free PMC article

Abstract

One of the fundamental challenges facing the cell is to accurately copy its genetic material to daughter cells. When this process goes awry, genomic instability ensues in which genetic alterations ranging from nucleotide changes to chromosomal translocations and aneuploidy occur. Organisms have developed multiple mechanisms that can be classified into two major classes to ensure the fidelity of DNA replication. The first class includes mechanisms that prevent premature initiation of DNA replication and ensure that the genome is fully replicated once and only once during each division cycle. These include cyclin-dependent kinase (CDK)-dependent mechanisms and CDK-independent mechanisms. Although CDK-dependent mechanisms are largely conserved in eukaryotes, higher eukaryotes have evolved additional mechanisms that seem to play a larger role in preventing aberrant DNA replication and genome instability. The second class ensures that cells are able to respond to various cues that continuously threaten the integrity of the genome by initiating DNA-damage-dependent "checkpoints" and coordinating DNA damage repair mechanisms. Defects in the ability to safeguard against aberrant DNA replication and to respond to DNA damage contribute to genomic instability and the development of human malignancy. In this article, we summarize our current knowledge of how genomic instability arises, with a particular emphasis on how the DNA replication process can give rise to such instability.

Figures

Figure 1.
Figure 1.
Cell-cycle-dependent regulation of prereplication complex (pre-RC). Pre-RCs are established immediately following exit from mitosis and are prevented from being assembled again from the G1/S transition until exit from the next mitotic cycle. This regulation is dependent primarily on CDK, which is maintained at low levels early in G1, but peaks to high levels at the G1/S, during S, G2, and M phases. Low CDK activity during G1 results from the APCCdc20-dependent proteolysis of M-phase cyclins and the accumulation of CDK inhibitors. High CDK activity, mediated by S-, G2-, or M-type cyclin, suppresses pre-RC through inactivation of multiple pre-RC components. In higher eukaryotes, pre-RC formation in S and G2/M is further inhibited by geminin, a specific inhibitor of the replication-licensing factor Cdt1, as well as by an S-phase-specific ubiquitin ligase, CRL4Dtl/Cdt2, which promotes the proteolysis of chromatin-bound Cdt1 and Set8.
Figure 2.
Figure 2.
Multiple mechanisms suppress DNA rereplication. In all eukaryotic organisms, CDK activity, in S, G2, and M phases of the cell cycle, inhibits rereplication by inactivating multiple components of the prereplication complex (pre-RC) to prevent reinitatiation of DNA replication. CDK directly phosphorylates origin recognition complex (ORC) proteins, Cdc6, Cdt1, as well as various subunits of the replicative helicase MCM2-7, resulting either in their targeted proteolysis or cytoplasmic sequestration and hence their inactivation (see text for details). Higher eukaryotes evolved additional CDK-independent mechanisms to suppress DNA rereplication in the more complex genomes. These include a specialized E3 ubiquitin ligase complex, CRL4Dtl/Cdt2, which promotes the destruction of PCNA- and chromatin-bound Cdt1, Set8, and p21 during S phase of the cell cycle as well as in response to DNA damage. In addition, geminin, which is expressed in S and G2 phases of the cell cycle, binds to and inhibits Cdt1 to prevent pre-RC assembly. The tumor suppressor p53 provides an additional barrier to DNA rereplication or to cell survival after rereplication, presumably owing to inhibition of S and G2/M CDK kinase through the transcriptional up-regulation of p21, the induction of intra-S and G2/M cell-cycle arrest, and the induction of apoptosis.
Figure 3.
Figure 3.
Model depicting cellular response to double-strand breaks (DSBs) and stalled replication forks. (A) Response to DSB: Mre11, Rad50, and Nbs1 complex (MRN) recognize DSBs and recruit ATM to the site where ATM signaling mediates repair by nonhomologous end joining (NHEJ) or homologous recombination (HR) while also inhibiting cyclin-dependent kinase (CDK) activity. (B) Response to stalled replication forks: Stalling of the replication machinery recruits ATR whose activity is required to prevent dissociation of the DNA polymerase complex. In addition, precocious HR is prevented and CDK activity at late firing replication origins is inhibited. (C) Dissociation of the replication machinery results in a collapsed fork. This may lead to a one-ended DSB, which can invade a sister chromatid to initiate replication restart.

Similar articles

See all similar articles

Cited by 61 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback