Abstract
During each cell duplication, the entirety of the genomic DNA in every cell must be accurately and quickly copied. Given the short time available for the chore, the requirement of many proteins, and the daunting amount of DNA present, DNA replication poses a serious challenge to the cell. A high level of coordination between polymerases and other DNA and chromatin-interacting proteins is vital to complete this task. One of the most important proteins for maintaining such coordination is PCNA. PCNA is a multitasking protein that forms a homotrimeric ring that encircles the DNA. It serves as a processivity factor for DNA polymerases and acts as a landing platform for different proteins interacting with DNA and chromatin. Therefore, PCNA is a signaling hub that influences the rate and accuracy of DNA replication, regulates DNA damage repair, controls chromatin formation during the replication, and the proper segregation of the sister chromatids. With so many essential roles, PCNA recruitment and turnover on the chromatin is of utmost importance. Three different, conserved protein complexes are in charge of loading/unloading PCNA onto DNA. Replication factor C (RFC) is the canonical complex in charge of loading PCNA during the S-phase. The Ctf18 and Elg1 (ATAD5 in mammalian) proteins form complexes similar to RFC, with particular functions in the cell’s nucleus. Here we summarize our current knowledge about the roles of these important factors in yeast and mammals.
Highlights
Proper functioning of all cells and organisms requires a stable genome that can withstand internal attacks and external genotoxic insults
A strain carrying both mutations at the SIM motif and in threonines 386-387 completely resembles an ELG1 deletion regarding high recombination rate, accumulation of SUMOylated PCNA, and DNA damage sensitivity [45]. These results suggest that PCNA and Elg1 have two interaction points, one at or near TT386/7 and one facilitated by interaction between SUMOylated PCNA and the SIM of Elg1 [45]
Epsilon is tethered to the moving fork by a physical interaction with the CMG, what role exactly does PCNA serve in the leading strand? New evidence suggests its roles are related to other processes, such as chromatin formation and sister chromatid establishment, which are carried out concomitantly with DNA replication
Summary
Proper functioning of all cells and organisms requires a stable genome that can withstand internal attacks (such as lesions created by oxidative damage) and external genotoxic insults (chemicals and radiation that may cause DNA lesions). The effect seen in elg1∆ strains is not due to the lack of Elg protein but the lack of Elg activity This arguably means that the unloading of PCNA from the lagging strand by the Elg1-RLC is required to elicit the DDR, at least in this simplified system, and this may be controlled by phosphorylation of the RLC’s large subunit. Ctf in cells with no Dun is not related to PCNA loading or unloading, but rather to its slowing-down of the replication fork: when all histones are hyper-acetylated, cells cannot distinguish between unreplicated DNA (before the moving fork, and usually wrapped around not acetylated histones) and already replicated DNA (behind the fork, wrapped around acetylated H3K56) Under these circumstances, Rad is induced, preventing firing from late origins. Rad24∆ cells are not defective in DNA damage repair itself, but in the activation of the DDR [88,89]
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