Replication licensing and cancer--a fatal entanglement?

Abstract

Correct regulation of the replication licensing system ensures that chromosomal DNA is precisely duplicated in each cell division cycle. Licensing proteins are inappropriately expressed at an early stage of tumorigenesis in a wide variety of cancers. Here we discuss evidence that misregulation of replication licensing is a consequence of oncogene-induced cell proliferation. This misregulation can cause either under- or over-replication of chromosomal DNA, and could explain the genetic instability commonly seen in cancer cells.

Figure 1

Overview of origin licensing during the cell division cycle. A small segment of chromosomal DNA, encompassing 3 replication origins is shown during the cell cycle. Mcm2-7 complexes (here shown as a double hexamer) are loaded onto origins during G1 when the licensing system is active (green). During S phase, Mcm2-7 complexes at licensed origins are activated to from part of the replication fork. When replication forks terminate, Mcm2-7 is displaced from the DNA. Prior to entry into S phase, the licensing system is shut down (pink shading) so Mcm2-7 cannot be loaded onto unreplicated DNA. This occurs as a consequence of geminin activation and Cdt1 degradation during S and G2, plus high CDK activity during mitosis. On exit from the cell cycle into G0, terminal differentiation or senescence, the licensing system is inactivated and Mcm2-7 are degraded.

Figure 2

Mcm5 in normal and dysplastic cervical epithelium. Frozen sections of normal cervix (a), low-grade (b) and high-grade (c) squamous intraepithelial lesions stained with antibodies against Mcm5. Magnification x108. Reproduced from .

Figure 3

The DNA damage response. Cartoon summarising major components of the DNA damage response (DDR) system that are active during S phase. Defects occurring at the DNA are sensed, and through the activation of the signal transducers leads to cellular responses.

Figure 4

Consequences of re-replication A small segment of chromosomal DNA containing a replication origin is shown. (a) A single re-initiation event generates a bubble of re-replicated DNA. If the rate of re-initiation is high, forks be initiated sufficiently close together that they undergo head-to-tail collision (b-c). The resultant bubble structures (d) may undergo recombination to form either extrachromosomal circles (e) or tandem chromosomal duplications (f). (Lines in (a-c) indicate single DNA strands, lines in (d-f) indicate double DNA strands.

Figure 5

Dormant origins and replication fork stalling. A small section of chromosomal DNA replicated by 2-3 origins is shown. Mcm2-7 double hexamers are shown as a pink oval. (a) If two converging forks stall with no dormant origin between them, the result is likely to be DNA breakage or rescue by recombination. (b) In the absence of fork stalling, the dormant origin between the two active origins does not initiate, and its Mcm2-7 proteins are passively displaced as they are replicated. (c) If the converging forks stall, the dormant origin between them can initiate and allow complete replication of the chromosomal segment.