G4-Interacting DNA Helicases and Polymerases: Potential Therapeutic Targets

Estep, Katrina N; Butler, Thomas J.; Ding, Jun; Brosh, Robert M.

doi:10.2174/0929867324666171116123345

Cited by 49 publications

(39 citation statements)

References 136 publications

(138 reference statements)

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“…[11][12][13][14][15][16] Additionally, due to their stability, G4 structures can challenge DNA replication and must be unfolded by proteins (eg, helicases). [17][18][19] In the absence of regulating proteins, the replication fork stalls at G4 motifs, leading to deletions or mutations. [20][21][22][23][24] Whereas the precise replication of G4 motifs is essential, it is not clear how the replication machinery recognizes these obstacles and how and why replication sometimes stalls approaching G4 motifs.…”

Section: Introductionmentioning

confidence: 99%

“…Regardless of topology, G4 structures were demonstrated to act as regulatory elements during transcription or telomere maintenance 11‐16 . Additionally, due to their stability, G4 structures can challenge DNA replication and must be unfolded by proteins (eg, helicases) 17‐19 . In the absence of regulating proteins, the replication fork stalls at G4 motifs, leading to deletions or mutations 20‐24 .…”

Section: Introductionmentioning

confidence: 99%

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Mgs1 protein supports genome stability via recognition of G‐quadruplex DNA structures

et al. 2020

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The integrity of the genetic material is crucial for every organism. One intrinsic attack to genome stability is stalling of the replication fork which can result in DNA breakage. Several factors, such as DNA lesions or the formation of stable secondary structures (eg, G‐quadruplexes) can lead to replication fork stalling. G‐quadruplexes (G4s) are well‐characterized stable secondary DNA structures that can form within specific single‐stranded DNA sequence motifs and have been shown to block/pause the replication machinery. In most genomes several helicases have been described to regulate G4 unfolding to preserve genome integrity, however, different experiments raise the hypothesis that processing of G4s during DNA replication is more complex and requires additional, so far unknown, proteins. Here, we show that the Saccharomyces cerevisiae Mgs1 protein robustly binds to G4 structures in vitro and preferentially acts at regions with a strong potential to form G4 structures in vivo. Our results suggest that Mgs1 binds to G4‐forming sites and has a role in the maintenance of genome integrity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mgs1 protein supports genome stability via recognition of G‐quadruplex DNA structures

et al. 2020

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“…During BER, G4 structure formation has been suggested to be stimulated by ROS-mediated oxidation of DNA and APE1 binding, which results in changes in transcription 33 , 34 . In eukaryotes, the polymerases Rev1, η , κ, and θ are involved in the replication of G4 motifs during TLS (reviewed in 66 ). The helicases XPB and XPD of the NER pathway have been shown to act at G4 sites by ChIP-seq 32 .…”

Section: Discussionmentioning

confidence: 99%

Zuo1 supports G4 structure formation and directs repair toward nucleotide excision repair

et al. 2020

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Nucleic acids can fold into G-quadruplex (G4) structures that can fine-tune biological processes. Proteins are required to recognize G4 structures and coordinate their function. Here we identify Zuo1 as a novel G4-binding protein in vitro and in vivo. In vivo in the absence of Zuo1 fewer G4 structures form, cell growth slows and cells become UV sensitive. Subsequent experiments reveal that these cellular changes are due to reduced levels of G4 structures. Zuo1 function at G4 structures results in the recruitment of nucleotide excision repair (NER) factors, which has a positive effect on genome stability. Cells lacking functional NER, as well as Zuo1, accumulate G4 structures, which become accessible to translesion synthesis. Our results suggest a model in which Zuo1 supports NER function and regulates the choice of the DNA repair pathway nearby G4 structures.

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“…Although beyond the scope of this review, biological and molecular evidence suggest that certain DNA helicases preserve genomic stability and maintain cellular homeostasis by resolving such alternate DNA structures. G4-resolving helicases are discussed in recent reviews [78,79]. A seminal study from the Lansdorp laboratory first suggested that a putative DNA helicase known as DOG-1 in C. elegans suppressed the accumulation of G4 structures in the lagging strand ssDNA template thereby preventing deletions in regions of the genome characterized by guanine-rich DNA [80].…”

Section: Helicases Resolve Unconventional Dna Structuresmentioning

confidence: 99%

History of DNA Helicases

Brosh

Matson

2020

Genes

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Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970’s to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field – where it has been, its current state, and where it is headed.

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G4-Interacting DNA Helicases and Polymerases: Potential Therapeutic Targets

Cited by 49 publications

References 136 publications

Mgs1 protein supports genome stability via recognition of G‐quadruplex DNA structures

Mgs1 protein supports genome stability via recognition of G‐quadruplex DNA structures

Zuo1 supports G4 structure formation and directs repair toward nucleotide excision repair

History of DNA Helicases

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