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DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (1 December 2019) | Viewed by 76020

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Dr. Robert Brosh

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Guest Editor

Section on DNA Helicases, Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, MD 21224, USA
Interests: helicase; DNA repair; replication; recombination; genomic stability; DNA metabolism; premature aging; chromosomal integrity

Special Issue Information

Dear Colleagues,

DNA helicases have emerged as a prominent class of nucleic acid metabolizing enzymes that play important roles in genome maintenance and cellular homeostasis. DNA helicases not only play essential roles in replication, DNA repair and recombination, they also influence gene expression and chromosome structure and act to resolve dynamic DNA structures that pose a source of genomic instability.

Although the basic mechanism of unwinding structured nucleic acids shares some basic commonality, research shows there are specialized DNA unwinding mechanisms that can be regulated by post-translational modifications and protein interactions.

With the discovery of genetic disorders linked to helicase gene mutations and various cancers associated with helicase defects, it has become more important than ever to characterize and document the molecular and cellular functions and pathways of DNA helicases to gain new understanding and move toward translational approaches in medicine.

This Special Issue of Genes will be dedicated to a compilation of articles on DNA helicases from leading experts in the field.

Dr. Robert Brosh
Guest Editor

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Keywords

helicase
replication
DNA repair
recombination
transcription
DNA structure
aging
cancer
genetic disease
genomic stability

Published Papers (14 papers)

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Editorial

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4 pages, 169 KiB

Open AccessEditorial

Special Issue: DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance

by Robert M. Brosh, Jr.

Genes 2021, 12(3), 356; https://doi.org/10.3390/genes12030356 - 01 Mar 2021

Cited by 2 | Viewed by 1767

Abstract

DNA helicases have emerged as a prominent class of nucleic acid-metabolizing enzymes that play important roles in genome maintenance and cellular homeostasis [...] Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

Research

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16 pages, 2393 KiB

Open AccessArticle

Assembly of a G-Quadruplex Repair Complex by the FANCJ DNA Helicase and the REV1 Polymerase

by Kaitlin Lowran, Laura Campbell, Phillip Popp and Colin G. Wu

Genes 2020, 11(1), 5; https://doi.org/10.3390/genes11010005 - 19 Dec 2019

Cited by 20 | Viewed by 7135

Abstract

The FANCJ helicase unfolds G-quadruplexes (G4s) in human cells to support DNA replication. This action is coupled to the recruitment of REV1 polymerase to synthesize DNA across from a guanine template. The precise mechanisms of these reactions remain unclear. While FANCJ binds to G4s with an AKKQ motif, it is not known whether this site recognizes damaged G4 structures. FANCJ also has a PIP-like (PCNA Interacting Protein) region that may recruit REV1 to G4s either directly or through interactions mediated by PCNA protein. In this work, we measured the affinities of a FANCJ AKKQ peptide for G4s formed by (TTAGGG)₄ and (GGGT)₄ using fluorescence spectroscopy and biolayer interferometry (BLI). The effects of 8-oxoguanine (8oxoG) on these interactions were tested at different positions. BLI assays were then performed with a FANCJ PIP to examine its recruitment of REV1 and PCNA. FANCJ AKKQ bound tightly to a TTA loop and was sequestered away from the 8oxoG. Reducing the loop length between guanine tetrads increased the affinity of the peptide for 8oxoG4s. FANCJ PIP targeted both REV1 and PCNA but favored interactions with the REV1 polymerase. The impact of these results on the remodeling of damaged G4 DNA is discussed herein. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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16 pages, 3398 KiB

Open AccessArticle

The Biochemical Activities of the Saccharomyces cerevisiae Pif1 Helicase Are Regulated by Its N-Terminal Domain

by David G. Nickens, Christopher W. Sausen and Matthew L. Bochman

Genes 2019, 10(6), 411; https://doi.org/10.3390/genes10060411 - 28 May 2019

Cited by 14 | Viewed by 3644

Abstract

Pif1 family helicases represent a highly conserved class of enzymes involved in multiple aspects of genome maintenance. Many Pif1 helicases are multi-domain proteins, but the functions of their non-helicase domains are poorly understood. Here, we characterized how the N-terminal domain (NTD) of the Saccharomyces cerevisiae Pif1 helicase affects its functions both in vivo and in vitro. Removal of the Pif1 NTD alleviated the toxicity associated with Pif1 overexpression in yeast. Biochemically, the N-terminally truncated Pif1 (Pif1ΔN) retained in vitro DNA binding, DNA unwinding, and telomerase regulation activities, but these activities differed markedly from those displayed by full-length recombinant Pif1. However, Pif1ΔN was still able to synergize with the Hrq1 helicase to inhibit telomerase activity in vitro, similar to full-length Pif1. These data impact our understanding of Pif1 helicase evolution and the roles of these enzymes in the maintenance of genome integrity. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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Review

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12 pages, 592 KiB

Open AccessReview

RECQ1 Helicase in Genomic Stability and Cancer

by Subrata Debnath and Sudha Sharma

Genes 2020, 11(6), 622; https://doi.org/10.3390/genes11060622 - 05 Jun 2020

Cited by 17 | Viewed by 3472

Abstract

RECQ1 (also known as RECQL or RECQL1) belongs to the RecQ family of DNA helicases, members of which are linked with rare genetic diseases of cancer predisposition in humans. RECQ1 is implicated in several cellular processes, including DNA repair, cell cycle and growth, telomere maintenance, and transcription. Earlier studies have demonstrated a unique requirement of RECQ1 in ensuring chromosomal stability and suggested its potential involvement in tumorigenesis. Recent reports have suggested that RECQ1 is a potential breast cancer susceptibility gene, and missense mutations in this gene contribute to familial breast cancer development. Here, we provide a framework for understanding how the genetic or functional loss of RECQ1 might contribute to genomic instability and cancer. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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10 pages, 889 KiB

Open AccessReview

Genome Maintenance by DNA Helicase B

by Lindsey Hazeslip, Maroof Khan Zafar, Muhammad Zain Chauhan and Alicia K. Byrd

Genes 2020, 11(5), 578; https://doi.org/10.3390/genes11050578 - 21 May 2020

Cited by 9 | Viewed by 3645

Abstract

DNA Helicase B (HELB) is a conserved helicase in higher eukaryotes with roles in the initiation of DNA replication and in the DNA damage and replication stress responses. HELB is a predominately nuclear protein in G₁ phase where it is involved in initiation of DNA replication through interactions with DNA topoisomerase 2-binding protein 1 (TOPBP1), cell division control protein 45 (CDC45), and DNA polymerase α-primase. HELB also inhibits homologous recombination by reducing long-range end resection. After phosphorylation by cyclin-dependent kinase 2 (CDK2) at the G₁ to S transition, HELB is predominately localized to the cytosol. However, this cytosolic localization in S phase is not exclusive. HELB has been reported to localize to chromatin in response to replication stress and to localize to the common fragile sites 16D (FRA16D) and 3B (FRA3B) and the rare fragile site XA (FRAXA) in S phase. In addition, HELB is phosphorylated in response to ionizing radiation and has been shown to localize to chromatin in response to various types of DNA damage, suggesting it has a role in the DNA damage response. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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18 pages, 2359 KiB

Open AccessReview

The Regulation of Homologous Recombination by Helicases

by Eric Huselid and Samuel F. Bunting

Genes 2020, 11(5), 498; https://doi.org/10.3390/genes11050498 - 01 May 2020

Cited by 23 | Viewed by 5394

Abstract

Homologous recombination is essential for DNA repair, replication and the exchange of genetic material between parental chromosomes during meiosis. The stages of recombination involve complex reorganization of DNA structures, and the successful completion of these steps is dependent on the activities of multiple helicase enzymes. Helicases of many different families coordinate the processing of broken DNA ends, and the subsequent formation and disassembly of the recombination intermediates that are necessary for template-based DNA repair. Loss of recombination-associated helicase activities can therefore lead to genomic instability, cell death and increased risk of tumor formation. The efficiency of recombination is also influenced by the ‘anti-recombinase’ effect of certain helicases, which can direct DNA breaks toward repair by other pathways. Other helicases regulate the crossover versus non-crossover outcomes of repair. The use of recombination is increased when replication forks and the transcription machinery collide, or encounter lesions in the DNA template. Successful completion of recombination in these situations is also regulated by helicases, allowing normal cell growth, and the maintenance of genomic integrity. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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18 pages, 3929 KiB

Open AccessReview

DNA Helicase-SSB Interactions Critical to the Regression and Restart of Stalled DNA Replication Forks in Escherichia coli

by Piero R. Bianco

Genes 2020, 11(5), 471; https://doi.org/10.3390/genes11050471 - 26 Apr 2020

Cited by 14 | Viewed by 3818

Abstract

In Escherichia coli, DNA replication forks stall on average once per cell cycle. When this occurs, replisome components disengage from the DNA, exposing an intact, or nearly intact fork. Consequently, the fork structure must be regressed away from the initial impediment so that repair can occur. Regression is catalyzed by the powerful, monomeric DNA helicase, RecG. During this reaction, the enzyme couples unwinding of fork arms to rewinding of duplex DNA resulting in the formation of a Holliday junction. RecG works against large opposing forces enabling it to clear the fork of bound proteins. Following subsequent processing of the extruded junction, the PriA helicase mediates reloading of the replicative helicase DnaB leading to the resumption of DNA replication. The single-strand binding protein (SSB) plays a key role in mediating PriA and RecG functions at forks. It binds to each enzyme via linker/OB-fold interactions and controls helicase-fork loading sites in a substrate-dependent manner that involves helicase remodeling. Finally, it is displaced by RecG during fork regression. The intimate and dynamic SSB-helicase interactions play key roles in ensuring fork regression and DNA replication restart. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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21 pages, 3010 KiB

Open AccessReview

TWINKLE and Other Human Mitochondrial DNA Helicases: Structure, Function and Disease

by Bradley Peter and Maria Falkenberg

Genes 2020, 11(4), 408; https://doi.org/10.3390/genes11040408 - 09 Apr 2020

Cited by 37 | Viewed by 9469

Abstract

Mammalian mitochondria contain a circular genome (mtDNA) which encodes subunits of the oxidative phosphorylation machinery. The replication and maintenance of mtDNA is carried out by a set of nuclear-encoded factors—of which, helicases form an important group. The TWINKLE helicase is the main helicase in mitochondria and is the only helicase required for mtDNA replication. Mutations in TWINKLE cause a number of human disorders associated with mitochondrial dysfunction, neurodegeneration and premature ageing. In addition, a number of other helicases with a putative role in mitochondria have been identified. In this review, we discuss our current knowledge of TWINKLE structure and function and its role in diseases of mtDNA maintenance. We also briefly discuss other potential mitochondrial helicases and postulate on their role(s) in mitochondria. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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Graphical abstract

45 pages, 2020 KiB

Open AccessFeature PaperEditor’s ChoiceReview

History of DNA Helicases

by Robert M. Brosh, Jr. and Steven W. Matson

Genes 2020, 11(3), 255; https://doi.org/10.3390/genes11030255 - 27 Feb 2020

Cited by 55 | Viewed by 12194

Abstract

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. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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12 pages, 2376 KiB

Open AccessReview

RECQ5: A Mysterious Helicase at the Interface of DNA Replication and Transcription

by Martin Andrs, Zdenka Hasanova, Anna Oravetzova, Jana Dobrovolna and Pavel Janscak

Genes 2020, 11(2), 232; https://doi.org/10.3390/genes11020232 - 21 Feb 2020

Cited by 16 | Viewed by 4995

Abstract

RECQ5 belongs to the RecQ family of DNA helicases. It is conserved from Drosophila to humans and its deficiency results in genomic instability and cancer susceptibility in mice. Human RECQ5 is known for its ability to regulate homologous recombination by disrupting RAD51 nucleoprotein filaments. It also binds to RNA polymerase II (RNAPII) and negatively regulates transcript elongation by RNAPII. Here, we summarize recent studies implicating RECQ5 in the prevention and resolution of transcription-replication conflicts, a major intrinsic source of genomic instability during cancer development. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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22 pages, 2352 KiB

Open AccessReview

Yeast Genome Maintenance by the Multifunctional PIF1 DNA Helicase Family

by Julius Muellner and Kristina H. Schmidt

Genes 2020, 11(2), 224; https://doi.org/10.3390/genes11020224 - 20 Feb 2020

Cited by 29 | Viewed by 5424

Abstract

The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility. ScPif1 and its fission yeast homolog Pfh1 also localize to mitochondria where they protect mitochondrial genome integrity. In addition to yeast serving as a model system for the rapid functional evaluation of human Pif1 variants, yeast cells lacking Rrm3 have proven useful for elucidating the cellular response to replication fork pausing at endogenous sites. Here, we review the increasingly important cellular functions of the yeast PIF1 helicases in maintaining genome integrity, and highlight recent advances in our understanding of their roles in facilitating fork progression through replisome barriers, their functional interactions with DNA repair, and replication stress response pathways. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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28 pages, 3079 KiB

Open AccessReview

Maintenance of Yeast Genome Integrity by RecQ Family DNA Helicases

by Sonia Vidushi Gupta and Kristina Hildegard Schmidt

Genes 2020, 11(2), 205; https://doi.org/10.3390/genes11020205 - 18 Feb 2020

Cited by 13 | Viewed by 4942

Abstract

With roles in DNA repair, recombination, replication and transcription, members of the RecQ DNA helicase family maintain genome integrity from bacteria to mammals. Mutations in human RecQ helicases BLM, WRN and RecQL4 cause incurable disorders characterized by genome instability, increased cancer predisposition and premature adult-onset aging. Yeast cells lacking the RecQ helicase Sgs1 share many of the cellular defects of human cells lacking BLM, including hypersensitivity to DNA damaging agents and replication stress, shortened lifespan, genome instability and mitotic hyper-recombination, making them invaluable model systems for elucidating eukaryotic RecQ helicase function. Yeast and human RecQ helicases have common DNA substrates and domain structures and share similar physical interaction partners. Here, we review the major cellular functions of the yeast RecQ helicases Sgs1 of Saccharomyces cerevisiae and Rqh1 of Schizosaccharomyces pombe and provide an outlook on some of the outstanding questions in the field. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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19 pages, 1613 KiB

Open AccessReview

DNA Helicases as Safekeepers of Genome Stability in Plants

by Annika Dorn and Holger Puchta

Genes 2019, 10(12), 1028; https://doi.org/10.3390/genes10121028 - 10 Dec 2019

Cited by 11 | Viewed by 4671

Abstract

Genetic information of all organisms is coded in double-stranded DNA. DNA helicases are essential for unwinding this double strand when it comes to replication, repair or transcription of genetic information. In this review, we will focus on what is known about a variety of DNA helicases that are required to ensure genome stability in plants. Due to their sessile lifestyle, plants are especially exposed to harmful environmental factors. Moreover, many crop plants have large and highly repetitive genomes, making them absolutely dependent on the correct interplay of DNA helicases for safeguarding their stability. Although basic features of a number of these enzymes are conserved between plants and other eukaryotes, a more detailed analysis shows surprising peculiarities, partly also between different plant species. This is additionally of high relevance for plant breeding as a number of these helicases are also involved in crossover control during meiosis and influence the outcome of different approaches of CRISPR/Cas based plant genome engineering. Thus, gaining knowledge about plant helicases, their interplay, as well as the manipulation of their pathways, possesses the potential for improving agriculture. In the long run, this might even help us cope with the increasing obstacles of climate change threatening food security in completely new ways. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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16 pages, 3826 KiB

Open AccessReview

Helicases FANCJ, RTEL1 and BLM Act on Guanine Quadruplex DNA in Vivo

by Peter Lansdorp and Niek van Wietmarschen

Genes 2019, 10(11), 870; https://doi.org/10.3390/genes10110870 - 31 Oct 2019

Cited by 28 | Viewed by 4182

Abstract

Guanine quadruplex (G4) structures are among the most stable secondary DNA structures that can form in vitro, and evidence for their existence in vivo has been steadily accumulating. Originally described mainly for their deleterious effects on genome stability, more recent research has focused on (potential) functions of G4 structures in telomere maintenance, gene expression, and other cellular processes. The combined research on G4 structures has revealed that properly regulating G4 DNA structures in cells is important to prevent genome instability and disruption of normal cell function. In this short review we provide some background and historical context of our work resulting in the identification of FANCJ, RTEL1 and BLM as helicases that act on G4 structures in vivo. Taken together these studies highlight important roles of different G4 DNA structures and specific G4 helicases at selected genomic locations and telomeres in regulating gene expression and maintaining genome stability. Full article

(This article belongs to the Special Issue DNA Helicases: Mechanisms, Biological Pathways, and Disease Relevance)

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