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Results for “flap endonuclease”

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PubMed2015

Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex.

During nuclear DNA replication, proofreading-deficient DNA polymerase α (Pol α) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol δ or Pol ε. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol α replication errors in a MutSα-dependent, MutLα-independent mismatch repair process we call Pol α-segment error editing (AEE). We show that MSH2 interacts with FEN1 and facilitates its nuclease activity to remove mismatches near the 5' ends of DNA substrates. Mouse cells and mice encoding FEN1 mutations display AEE deficiency, a strong mutator phenotype, enhanced cellular transformation, and increased cancer susceptibility. The results identify a novel role for FEN1 in a specialized mismatch repair pathway and a new cancer etiological mechanism.

Animals↗
PubMed2026

DNA polymerase I: structure, activity, and function in bacterial DNA replication and repair.

Faithful replication and repair of the genome are essential processes for all life. Genome maintenance is coordinated by a complex suite of proteins, with bacteria evolving intricate systems despite their relatively simplistic genomes. DNA polymerases are a key class of proteins that mediate genome maintenance. DNA polymerases are all capable of extending nascent strands of DNA but contribute to DNA replication and repair in distinct ways depending on their active site and substrate specificity. The first discovered polymerase, bacterial DNA polymerase I (Pol I), has long been considered the primary enzyme responsible for Okazaki fragment maturation and resynthesis in many DNA repair pathways. These conclusions derive primarily from studies using the gram-negative bacterium, Escherichia coli. Given that some bacterial lineages diverged from E. coli over a billion years ago, these assumptions may not account for evolution in functional diversity. In this review, we examine the structural features of bacterial Pol I and discuss how each of its distinct enzymatic activities contribute to genome maintenance. Throughout, we introduce differences that have been discovered between gram-negative and gram-positive species and explore how activity differences may translate to functional adaptations in replication or repair. We focus on evidence from gram-positive bacteria, particularly Bacillus subtilis and Geobacillus stearothermophilus, that challenges the universality of Pol I's functions and reveals lineage-specific adaptations in replication and repair mechanisms. By synthesizing historical perspectives with recent discoveries, this review underscores both the importance of Pol I and the evolutionary diversification of Pol I in bacterial DNA metabolism.

Bacterial DNA replication↗