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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

G4-Interacting DNA Helicases and Polymerases: Potential Therapeutic Targets

Author(s): Katrina N. Estep, Thomas J. Butler, Jun Ding and Robert M. Brosh*

Volume 26, Issue 16, 2019

Page: [2881 - 2897] Pages: 17

DOI: 10.2174/0929867324666171116123345

Price: $65

Abstract

Background: Guanine-rich DNA can fold into highly stable four-stranded DNA structures called G-quadruplexes (G4). In recent years, the G-quadruplex field has blossomed as new evidence strongly suggests that such alternately folded DNA structures are likely to exist in vivo. G4 DNA presents obstacles for the replication machinery, and both eukaryotic DNA helicases and polymerases have evolved to resolve and copy G4 DNA in vivo. In addition, G4-forming sequences are prevalent in gene promoters, suggesting that G4-resolving helicases act to modulate transcription.

Methods: We have searched the PubMed database to compile an up-to-date and comprehensive assessment of the field’s current knowledge to provide an overview of the molecular interactions of Gquadruplexes with DNA helicases and polymerases implicated in their resolution.

Results: Novel computational tools and alternative strategies have emerged to detect G4-forming sequences and assess their biological consequences. Specialized DNA helicases and polymerases catalytically act upon G4-forming sequences to maintain normal replication and genomic stability as well as appropriate gene regulation and cellular homeostasis. G4 helicases also resolve telomeric repeats to maintain chromosomal DNA ends. Bypass of many G4-forming sequences is achieved by the action of translesion DNS polymerases or the PrimPol DNA polymerase. While the collective work has supported a role of G4 in nuclear DNA metabolism, an emerging field centers on G4 abundance in the mitochondrial genome.

Conclusion: Discovery of small molecules that specifically bind and modulate DNA helicases and polymerases or interact with the G4 DNA structure itself may be useful for the development of anticancer regimes.

Keywords: G-quadruplex, replication, helicase, polymerase, translesion synthesis, G4 DNA, PrimPol.

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