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Review
. 2010 Apr;11(4):270-8.
doi: 10.1038/embor.2010.27. Epub 2010 Feb 26.

Differences in the DNA replication of unicellular eukaryotes and metazoans: known unknowns

Alessia Errico  1 , Vincenzo Costanzo
Affiliations
Review

Differences in the DNA replication of unicellular eukaryotes and metazoans: known unknowns

Alessia Errico et al. EMBO Rep. 2010 Apr.

Abstract

Although the basic mechanisms of DNA synthesis are conserved across species, there are differences between simple and complex organisms. In contrast to lower eukaryotes, replication origins in complex eukaryotes lack DNA sequence specificity, can be activated in response to stressful conditions and require poorly conserved factors for replication firing. The response to replication fork damage is monitored by conserved proteins, such as the TIPIN-TIM-CLASPIN complex. The absence of this complex induces severe effects on yeast replication, whereas in higher eukaryotes it is only crucial when the availability of replication origins is limiting. Finally, the dependence of DNA replication on homologous recombination proteins such as RAD51 and the MRE11-RAD50-NBS1 complex is also different; they are dispensable for yeast S-phase but essential for accurate DNA replication in metazoans under unchallenged conditions. The reasons for these differences are not yet understood. Here, we focus on some of these known unknowns of DNA replication.

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Figures

Figure 1
Figure 1
The organization of replication origins. The number of MCM2–7 complexes loaded onto chromatin is in excess compared with ORC1–6. When a replication fork stalls (a), a nearby dormant origin (green circle) can be activated to resume DNA replication. If DNA replication continues unperturbed (b), dormant origins are replicated passively by the active replicon. CDC, cell division control; CDK, cyclin-dependent kinase; MCM, minichromosome maintenance protein; ORC, origin recognition complex.
Figure 2
Figure 2
Initial steps of DNA replication in yeast and metazoans. Orc1–6 defines the origins of replication. (A) In yeast, the loading of the Mcm2–7 helicase is regulated through the action of Cdc6 and Cdt1. Sld2 and Sld3 are required for origin firing after phosphorylation by CDKs. (B) In higher eukaryotes, there is an additional level of regulation of MCM2–7 loading due to the presence of MCM9 and geminin. MCM8 is only present in higher eukaryotes and seems to facilitate fork progression. PLK1/Plx1 regulates DNA replication under stressful conditions, a role that has only been shown for higher eukaryotes. Cdc, cell division control; CDKs, cyclin-dependent kinases; Cdt1, chromatin licensing and DNA replication factor 1; Dpb11, DNA polymerase B (II); Mcm, minichromosome maintenance protein; ORC, origin recognition complex; Plx1, Xenopus Polo-like kinase 1; Sld, synthetic lethal with Dpb11–1; TOPBP1, DNA topoisomerase 2 binding protein 1.
Figure 3
Figure 3
The replication pausing complex. TIPIN–TIM1–AND1 might create a flexible bridge between replisome components such as CDC45, GINS, POLα and the MCM2–7 complex, which is required to stabilize POLα at replication forks. Mrc1 (CLASPIN) is also associated with TIPIN–TIM1 and is thought to couple Polɛ to the replisome. (a) When replication is halted, TIPIN–TIM1, AND1 and CLASPIN physically link the polymerase and helicase activities, preventing fork collapse. (b) The absence of these components could lead to excessive unwinding of DNA, thus destabilizing the replisome. AND1, acidic nucleoplasmic DNA-binding protein 1; CDC, cell division control; GINS, Go, Ichi, Ni and San complex; MCM, minichromosome maintenance protein; Mrc1, mediator of replication checkpoint 1; POLα/ɛ, polymerase-α/ɛ; TIM1, Timeless; TIPIN, Tim1-interacting protein.
Figure 4
Figure 4
Double-strand break repair pathways NHEJ, HR, BIR and MMBIR. (A) DSBs can be repaired by HR or NHEJ. (B) Replication forks collapse when they encounter a nick in the template, generating a DSB with only one end. The 5′ strand is then resected, which results in a 3′ overhang that can invade the sister molecule (blue) forming a D-loop, a process that is mediated by Rad51. The D-loop evolves in a replication fork with both leading and lagging strand synthesis. Whether BIR is resolved by cleavage of a Holliday junction or by helicase activity (separation step) is unknown. The separated end can dissociate and reinvade DNA templates, iterating the process until the replication of a chromosome segment is complete. (C) In MMBIR, microhomology-containing regions drive the strand invasion of non-sister templates, thereby leading to chromosomal rearrangements after a few rounds of invasion–replication–resolution. ATM, ataxia telangiectasia mutated; BIR, break-induced replication; DSB, double-strand break; HR, homologous recombination; MMBIR, microhomology-mediated BIR; NHEJ, non-homologous end-joining; Rad, radiation arrest deficient.
None
Alessia Errico
None
Vincenzo Costanzo
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