Eukaryotic Mismatch Repair in Relation to DNA Replication

Abstract

Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation, occasional mismatches that do form are proofread during replication, and rare mismatches that escape proofreading are corrected by mismatch repair (MMR). This review focuses on MMR in light of increasing knowledge about nuclear DNA replication enzymology and the rate and specificity with which mismatches are generated during leading- and lagging-strand replication. We consider differences in MMR efficiency in relation to mismatch recognition, signaling to direct MMR to the nascent strand, mismatch removal, and the timing of MMR. These studies are refining our understanding of relationships between generating and repairing replication errors to achieve accurate replication of both DNA strands of the nuclear genome.

The Devil is in the details for DNA mismatch repair

“…Whether HsMutLα also functions to limit loading of HsMutSα at a mismatch or renders an essential factor such as EXO1 limiting remains unknown. This stochastic sliding clamp model for MMR stands in contrast to models in which MMR proteins remain at the mismatch to license excision (1,9). Another paradox centers on the requirement for EXO1 in in vitro MMR reactions but its seemingly minor role in vivo (9).…”

“…This task requires an intricate network of cellular components that carries out replication and postreplication DNA repair (1). In eukaryotes, replication is carried out by Pol e and Pol δ that synthesize the leading and lagging strands, respectively, using short RNA-DNA primers synthesized by Pol α.…”

“…The nucleotide switch model posits the existence of multiple diffusing MSH-MLH clamps (8). Other studies suggest that a single MSH clamp at a mismatch can load multiple MLH clamps to license excision (1,9). MutSα (MSH2-MSH6) and MutSβ (MSH2-MSH3) are related to the AAA + family of ATPases and carry out mismatch recognition (10,11).…”

DNA Mismatch Repair Interacts with CAF-1- and ASF1A-H3-H4-dependent Histone (H3-H4)2 Tetramer Deposition

“…Genetic stabilization provided by the MMR system suppresses both sporadic and inherited cancers (4). The MMR system has multiple functions that are involved in the genome maintenance (1)(2)(3)(5)(6)(7)(8). Among these functions MMR is the strongest contributor to the suppression of spontaneous mutation rates.…”

“…One-nucleotide deletion loops, mispaired bases, and one-nucleotide insertion loops are the most common substrates for the eukaryotic MMR reaction (1,2,6,7). In addition to these lesions, the eukaryotic reaction removes oxidized bases, one-nucleotide flaps, and single ribonucleotides that produce mispairs in DNA (20 -23).…”