Abstract
During cell division, genome integrity is maintained by faithful DNA replication during S phase, followed by accurate segregation in mitosis. Many DNA metabolic events linked with DNA replication are also regulated throughout the cell cycle. In eukaryotes, the DNA sliding clamp, proliferating cell nuclear antigen (PCNA), acts on chromatin as a processivity factor for DNA polymerases. Since its discovery, many other PCNA binding partners have been identified that function during DNA replication, repair, recombination, chromatin remodeling, cohesion, and proteolysis in cell-cycle progression. PCNA not only recruits the proteins involved in such events, but it also actively controls their function as chromatin assembles. Therefore, control of PCNA-loading onto chromatin is fundamental for various replication-coupled reactions. PCNA is loaded onto chromatin by PCNA-loading replication factor C (RFC) complexes. Both RFC1-RFC and Ctf18-RFC fundamentally function as PCNA loaders. On the other hand, after DNA synthesis, PCNA must be removed from chromatin by Elg1-RFC. Functional defects in RFC complexes lead to chromosomal abnormalities. In this review, we summarize the structural and functional relationships among RFC complexes, and describe how the regulation of PCNA loading/unloading by RFC complexes contributes to maintaining genome integrity.
Highlights
These findings indicate that Ctf18-replication factor C (RFC) is primarily required for sister chromatid cohesion, and might be involved in the regulation of proliferating cell nuclear antigen (PCNA) on chromatin
Three independent groups demonstrated that Elg1‐RFC functions as the major PCNA unloader leads to an extreme accumulation of chromatin-bound PCNA and the corresponding PCNA foci are during DNA replication, in both yeast and mammalian cells [73,74,75]
Is Elg1-RFC the only PCNA unloader? Even in the absence of Elg1, the PCNA retained on the chromatin is eventually removed in the M phase [75]; the PCNA unloading function could conceivably be performed by RFC1-RFC and/or Ctf18-RFC, as suggested by their biochemical and genetic analyses
Summary
Complex), unwinds double-stranded DNA, and DNA polymerases are recruited for replication [3] Accompanying these events are several other important processes, including repair; recombination; chromatin formation, modification, and remodeling; as well as the maintenance of epigenetic information and the prevention of re-replication during replication fork progression. Sister chromatid cohesion must occur, as their alignment is required for faithful chromosome segregation [4,5] To carry out these various activities, the DNA replication fork requires many proteins that form a large complex, the replisome, to facilitate the efficient initiation and elongation of DNA synthesis and chromatin-associated events [6]. Among these proteins, in eukaryotes, the DNA sliding clamp. We highlight the role of the RFC complex as a PCNA loader or unloader that conducts replication-linked processes, and discuss how these functions are orchestrated to maintain genome integrity
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