Dna2 on the road to Okazaki fragment processing and genome stability in eukaryotes

@article{Kang2010Dna2OT,
  title={Dna2 on the road to Okazaki fragment processing and genome stability in eukaryotes},
  author={Young-Hoon Kang and Chul-Hwan Lee and Yeon-Soo Seo},
  journal={Critical Reviews in Biochemistry and Molecular Biology},
  year={2010},
  volume={45},
  pages={71 - 96}
}
DNA replication is a primary mechanism for maintaining genome integrity, but it serves this purpose best by cooperating with other proteins involved in DNA repair and recombination. Unlike leading strand synthesis, lagging strand synthesis has a greater risk of faulty replication for several reasons: First, a significant part of DNA is synthesized by polymerase α, which lacks a proofreading function. Second, a great number of Okazaki fragments are synthesized, processed and ligated per cell… 

Mechanism of Lagging-Strand DNA Replication in Eukaryotes.

This chapter focuses on the enzymes and mechanisms involved in lagging-strand DNA replication in eukaryotic cells and how each of the millions of Okazaki fragments in a mammalian cell is primed by the primase subunit and further extended by its polymerase sub unit.

Okazaki fragment metabolism.

Genetic analyses and reconstitution experiments identified proteins and multiple pathways responsible for maturation of the lagging strand, which involves many enzymes, possibly three pathways, and regulation that can shift from high efficiency to high fidelity.

The Saccharomyces cerevisiae Dna2 can function as a sole nuclease in the processing of Okazaki fragments in DNA replication

A model where Dna2 alone is responsible for cleaving of RPA-bound long flaps, while Fen1 or exonuclease 1 (Exo1) cleave short flaps is proposed, arguing that Dna1 can function in a separate, rather than in a Fen1-dependent pathway.

Eukaryotic DNA Replication Fork.

The preponderance of evidence supports a model in which DNA polymerase ε (Pol ε) carries out the bulk of leading strand DNA synthesis at an undisturbed replication fork, with an emphasis on the enzymes that synthesize DNA and repair discontinuities on the lagging strand of the replication fork.

Okazaki Fragment Processing-independent Role for Human Dna2 Enzyme during DNA Replication*

The findings suggest that the genomic instability observed in hDna2-depleted cells does not arise from defective OF maturation and that hDNA2 plays a role in DNA replication that is distinct from FEN1 and Of maturation.

Dna2 Exhibits a Unique Strand End-dependent Helicase Function*

This is the first description of a eukaryotic helicase that cannot load onto its tracking strand internally but instead must enter from the end, and likely helps the helicase to coordinate with the Dna2 nuclease function to prevent creation of undesirably long flaps during DNA transactions.

Rad53 arrests leading and lagging strand DNA synthesis via distinct mechanisms in response to DNA replication stress

  • Richard HeZhiguo Zhang
  • Biology
    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 2022
eSPAN and BrdU‐IP‐ssSeq, strand‐specific sequencing technologies that permit analysis of protein localization and DNA synthesis at individual strands in budding yeast, are discussed and it is shown that under replication stress Rad53 stalls DNA synthesis on both leading and lagging strands.

The wonders of flap endonucleases: structure, function, mechanism and regulation.

A detailed review of FEN structure is undertaken to show how DNA substrate recognition occurs and how FEN achieves cleavage at a single phosphate diester, and a proposed double nucleotide unpairing trap (DoNUT) is discussed with regards to FEN and has relevance to the wider 5' nuclease superfamily.

hDNA2 nuclease/helicase promotes centromeric DNA replication and genome stability

It is shown that DNA2 binds preferentially to centromeric DNA, and the DNA2 inhibitor C5 mimics DNA2 knockout and synergistically kills cancer cells when combined with an ATR inhibitor, providing mechanistic insights into how DNA2 supports replication of centromic DNA.

DNA2 in Chromosome Stability and Cell Survival—Is It All about Replication Forks?

It is proposed that the major cellular defects associated with DNA2 dysfunction, and the links that exist with human disease, can be rationalized through the fundamental importance of DNA2-dependent RF recovery to genome duplication.
...

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