RTEL1: functions of a disease-associated helicase

doi:10.1016/j.tcb.2014.01.004

Trends in Cell Biology

Volume 24, Issue 7, July 2014, Pages 416-425

https://doi.org/10.1016/j.tcb.2014.01.004 Get rights and content

Highlights

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RTEL1 is an Fe–S helicase that controls homologous recombination by dismantling D-loop intermediates.
•
RTEL1 maintains telomere integrity by disassembling T-loops and counteracting G4-DNA structures.
•
RTEL1 variants strongly associate with predisposition to glioma, astrocytoma, and glioblastoma.
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Mutations in RTEL1 give rise to Hoyeraal–Hreidarsson syndrome.

DNA secondary structures that arise during DNA replication, repair, and recombination (3R) must be processed correctly to prevent genetic instability. Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles a variety of DNA secondary structures to facilitate 3R processes and to maintain telomere integrity. The past few years have witnessed the emergence of RTEL1 variants that confer increased susceptibility to high-grade glioma, astrocytomas, and glioblastomas. Mutations in RTEL1 have also been implicated in Hoyeraal–Hreidarsson syndrome, a severe form of the bone-marrow failure and cancer predisposition disorder, dyskeratosis congenita. We review these recent findings and highlight its crucial link between DNA secondary-structure metabolism and human disease.

Section snippets

DNA secondary-structure metabolism during DNA replication and repair

The formation and/or metabolism of DNA secondary structures is important for many physiological processes, and is particularly relevant during DNA replication and repair (reviewed in [1]). However, persistent or aberrantly processed DNA secondary structures can have pathological consequences and are an established source of genome instability 2, 3. DNA secondary structures can form from alternative DNA sequence motifs [e.g., trinucleotide repeats, or G-rich DNA that forms four-stranded DNA

RTEL1 in telomere homeostasis

RTEL1 belongs to the DEAH (named from the corresponding four amino acid motif in single-letter code) subfamily of the superfamily 2 (SF2) helicases, which contain a RAD3-related DNA helicase domain with 5′ to 3′ helicase activity (reviewed in 19, 20). RTEL1 is also a member of the iron–sulfur (Fe–S) cluster helicase family, which includes xeroderma pigmentosum group D (XPD), Fanconi anemia complementation group J (FANCJ), and DEAD/H box helicase 11 (DDX11; reviewed in [21]). The activity of

RTEL1 controls recombination in mitotic and meiotic cells

RTEL1 was independently identified in C. elegans as a key regulator of HR in a genetic screen for synthetic lethality with mutation in the sgs1/BLM orthologue, which is associated with the accumulation of persistent recombination intermediates [28]. Consistent with a role for RTEL1 in suppressing HR (Figure 1), worms and human cells lacking RTEL1 exhibit hyper-recombination and sensitivity to DNA damaging agents. Moreover, C. elegans rtel-1 mutants are also synthetic lethal when combined with

RTEL1 controls recombination at telomeres

Visualization of vertebrate telomeres by electron microscopy and STORM (stochastic optical reconstruction microscopy) has revealed that some, if not all, chromosome ends adopt a lasso-like configuration called a T-loop 4, 33. The T-loop is proposed to form upon strand invasion of the 3′ ss TTAGGG telomeric repeats into an adjacent duplex of telomeric DNA, resulting in a D-loop intermediate at the site of strand invasion [34]. T-loops may protect the chromosome end from degradation and

RTEL1 is essential to facilitate replication

Several observations suggested a possible role for RTEL1 during DNA replication. Mouse ES cells deficient for RTEL1 exhibit reduced proliferative capacity, and worms and mammalian cells lacking RTEL1 are particularly sensitive to DNA damaging agents that hinder DNA replication, such as inter-strand crosslinking agents 25, 26, 28. Proteomic analysis of RTEL1 interacting proteins reinforced the link between RTEL1 and DNA replication, and identified multiple DNA replication factors, including

RTEL1 in human diseases

Mutations in XPD, FANCJ, and DDX11 have been shown to be an underlying cause of xeroderma pigmentosum (reviewed in [40]), Fanconi anemia 41, 42, 43, 44, and Warsaw breakage syndrome 45, 46, respectively. In the last few years, RTEL1 variants have also been linked to several distinct human brain cancers and recently, RTEL1 mutations have been shown to give rise to Hoyeraal–Hreidarsson syndrome, a severe form of the telomeropathy dyskeratosis congenita 14, 16, 17. Below we discuss the relevance

RTEL1 and cancer predisposition

Genome-wide association studies (GWAS) established an association of single-nucleotide polymorphisms (SNPs) in RTEL1 with increased susceptibility to brain tumours. A principal component-adjusted GWAS study, comprising over 275 000 autosomal variants among 692 adult glioma cases and 3992 controls, identified two SNPs within intron 12 (rs6010620) and intron 17 (rs4809324) of RTEL1 that are significantly associated with glioma and astrocytoma predisposition [47]. Similarly, two further glioma GWAS

RTEL1 and Hoyeraal–Hreidarsson syndrome

Telomere attrition, a natural biological process that arises from failure to maintain telomere homeostasis, has been linked to an elevated risk of a variety of age-related diseases (reviewed in 63, 64, 65, 66). Critically short telomeres signal the cell to terminate division and enter a stable cell cycle arrest termed senescence (reviewed in 67, 68). Mutations in genes encoding telomere-associated proteins give rise to premature aging disorders such as Werner Syndrome, Hoyeraal–Hreidarsson

Concluding remarks

Although recent insights into the function of RTEL1 in controlling HR, telomere homeostasis and facilitating DNA replication have highlighted its importance in the maintenance of genome stability, many outstanding questions remain to be addressed. Currently, very little is known about how RTEL1 is regulated or how it is recruited to replication forks and telomeres to execute its functions. The association of RTEL1 with the replisome is evident from its ability to bind directly to PCNA, but the

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Characterization of the Escherichia coli XPD/Rad3 iron-sulfur helicase YoaA in complex with the DNA polymerase III clamp loader subunit chi (χ)
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Escherichia coli YoaA aids in the resolution of DNA damage that halts DNA synthesis in vivo in conjunction with χ, an accessory subunit of DNA polymerase III. YoaA and χ form a discrete complex separate from the DNA polymerase III holoenzyme, but little is known about how YoaA and χ work together to help the replication fork overcome damage. Although YoaA is predicted to be an iron-sulfur helicase in the XPD/Rad3 helicase family based on sequence analysis, the biochemical activities of YoaA have not been described. Here, we characterize YoaA and show that purified YoaA contains iron. YoaA and χ form a complex that is stable through three chromatographic steps, including gel filtration chromatography. When overexpressed in the absence of χ, YoaA is mostly insoluble. In addition, we show the YoaA-χ complex has DNA-dependent ATPase activity. Our measurement of the YoaA-χ helicase activity illustrates for the first time YoaA-χ translocates on ssDNA in the 5ˈ to 3ˈ direction and requires a 5ˈ single-stranded overhang, or ssDNA gap, for DNA/DNA unwinding. Furthermore, YoaA-χ preferentially unwinds forked duplex DNA that contains both 3ˈ and 5ˈ single-stranded overhangs versus duplex DNA with only a 5ˈ overhang. Finally, we demonstrate YoaA-χ can unwind damaged DNA that contains an abasic site or damage on 3ˈ ends that stall replication extension. These results are the first biochemical evidence demonstrating YoaA is a bona fide iron-sulfur helicase, and we further propose the physiologically relevant form of the helicase is YoaA-χ.
Unwinding during stressful times: Mechanisms of helicases in meiotic recombination
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Successful meiosis I requires that homologous chromosomes be correctly linked before they are segregated. In most organisms this physical linkage is achieved through the generation of crossovers between the homologs. Meiotic recombination co-opts and modifies the canonical homologous recombination pathway to successfully generate crossovers One of the central components of this pathway are a number of conserved DNA helicases. Helicases couple nucleic acid binding to nucleotide hydrolysis and use this activity to modify DNA or protein-DNA substrates. During meiosis I it is necessary for the cell to modulate the canonical DNA repair pathways in order to facilitate the generation of interhomolog crossovers. Many of these meiotic modulations take place in pathways involving DNA helicases, or with a meiosis specific helicase. This short review explores what is currently understood about these helicases, their interaction partners, and the role of regulatory modifications during meiosis I. We focus in particular on the molecular structure and mechanisms of these helicases.
Alternative complexes formed by the Escherichia coli clamp loader accessory protein HolC (x) with replication protein HolD (ψ) and repair protein YoaA
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Citation Excerpt :
Eukaryotes and archaea possess multiple members of Fe-S cluster DNA helicase group [26,61] with similar functions in repair and maintenance of genomic stability. In humans, these pathways include excision repair and transcription-couple repair (XPD) [70], DNA cross-link repair (FANCJ, DDX11) [71,72], disassembly of DNA secondary structure and telomere maintenance (RTEL, FANCJ) [73,74], and homologous recombination (RTEL, DDX11) [72,74]. Defects in these underlie a number of genetic diseases, including XPD xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy; FANC-J, Fanconi anemia and breast cancer proneness; RTEL, Hoyeraal-Hreidarsson syndrome; DDX11, Warsaw breakage syndrome.
Efficient and faithful replication of DNA is essential for all organisms. However, the replication fork frequently encounters barriers that need to be overcome to ensure cell survival and genetic stability. Cells must carefully balance and regulate replication vs. repair reactions. In Escherichia coli, the replisome consists of the DNA polymerase III holoenzyme, including DNA polymerase, proofreading exonuclease, processivity clamp and clamp loader, as well as a fork helicase, DnaB and primase, DnaG. We provide evidence here that one component of the clamp loader complex, HolC (or χ) plays a dual role via its ability to form 2 mutually exclusive complexes: one with HolD (or ψ) that recruits the clamp-loader and hence the DNA polymerase holoenzyme and another with helicase-like YoaA protein, a DNA-damage inducible repair protein. By yeast 2 hybrid analysis, we show that two residues of HolC, F64 and W57, at the interface in the structure with HolD, are required for interaction with HolD and for interaction with YoaA. Mutation of these residues does not interfere with HolC’s interaction with single-strand DNA binding protein, SSB. In vivo, these mutations fail to complement the poor growth and sensitivity to azidothymidine, a chain-terminating replication inhibitor. In support of the notion that these are exclusive complexes, co-expression of HolC, HolD and YoaA, followed by pulldown of YoaA, yields a complex with HolC but not HolD. YoaA fails to pulldown HolC-F64A. We hypothesize that HolC, by binding with SSB, can recruit the DNA polymerase III holoenzyme through HolD, or an alternative repair complex with YoaA helicase.
Molecular mechanisms of telomere biology disorders
2021, Journal of Biological Chemistry
Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.
RTEL1 Regulates G4/R-Loops to Avert Replication-Transcription Collisions
2020, Cell Reports
Citation Excerpt :
Subsequent genome-wide association studies identified RTEL1 as a susceptibility locus for astrocytomas, high-grade gliomas, and many other cancers. Hypomorphic mutations in human RTEL1 are also causal for Hoyeraal-Hreidarsson syndrome (HHS), a severe disorder associated with inter-uterine growth retardation, microcephaly, bone marrow failure, immunodeficiency, and many other complications (for review, see Vannier et al., 2014). While the etiology of HHS remains to be fully elucidated, patient-derived cells and PIP box knockin mouse cells present with both telomeric attrition, increased replication stress, and reduced proliferative capacity in culture.
Regulator of telomere length 1 (RTEL1) is an essential helicase that maintains telomere integrity and facilitates DNA replication. The source of replication stress in Rtel1-deficient cells remains unclear. Here, we report that loss of RTEL1 confers extensive transcriptional changes independent of its roles at telomeres. The majority of affected genes in Rtel1^−/− cells possess G-quadruplex (G4)-DNA-forming sequences in their promoters and are similarly altered at a transcriptional level in wild-type cells treated with the G4-DNA stabilizer TMPyP4 (5,10,15,20-Tetrakis-(N-methyl-4-pyridyl)porphine). Failure to resolve G4-DNAs formed in the displaced strand of RNA-DNA hybrids in Rtel1^−/− cells is suggested by increased R-loops and elevated transcription-replication collisions (TRCs). Moreover, removal of R-loops by RNaseH1 overexpression suppresses TRCs and alleviates the global replication defects observed in Rtel1^−/− and Rtel1^PIP_box knockin cells and in wild-type cells treated with TMPyP4. We propose that RTEL1 unwinds G4-DNA/R-loops to avert TRCs, which is important to prevent global deregulation in both transcription and DNA replication.

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^*: These authors contributed equally.

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Trends in Cell Biology

ReviewRTEL1: functions of a disease-associated helicase

Highlights

Section snippets

DNA secondary-structure metabolism during DNA replication and repair

RTEL1 in telomere homeostasis

RTEL1 controls recombination in mitotic and meiotic cells

RTEL1 controls recombination at telomeres

RTEL1 is essential to facilitate replication

RTEL1 in human diseases

RTEL1 and cancer predisposition

RTEL1 and Hoyeraal–Hreidarsson syndrome

Concluding remarks

DNA secondary structures: stability and function of G-quadruplex structures

Nat. Rev. Genet.

Mutagenic capacity of endogenous G4 DNA underlies genome instability in FANCJ-defective C. elegans

Curr. Biol.

DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase

Cell

Mammalian telomeres end in a large duplex loop

Cell

Homologous recombination generates T-loop-sized deletions at human telomeres

Cell

Shelterin: the protein complex that shapes and safeguards human telomeres

Genes Dev.

A single-stranded DNA-binding protein is needed for efficient presynaptic complex formation by the Saccharomyces cerevisiae Rad51 protein

J. Biol. Chem.

Similarity of the yeast RAD51 filament to the bacterial RecA filament

Science

DNA strand exchange mediated by a RAD51–ssDNA nucleoprotein filament with polarity opposite to that of RecA

Cell

Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair

Cell

Sgs1 regulates gene conversion tract lengths and crossovers independently of its helicase activity

Mol. Cell. Biol.

BLAP75/RMI1 promotes the BLM-dependent dissolution of homologous recombination intermediates

Proc. Natl. Acad. Sci. U.S.A.

RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity

Cell

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal–Hreidarsson syndrome

PLoS Genet.

Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in dyskeratosis congenita

Hum. Genet.

Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome

Proc. Natl. Acad. Sci. U.S.A.

Human RTEL1 deficiency causes Hoyeraal–Hreidarsson syndrome with short telomeres and genome instability

Hum. Mol. Genet.

Constitutional mutations in RTEL1 cause severe dyskeratosis congenita

Am. J. Hum. Genet.

SF1 and SF2 helicases: family matters

Curr. Opin. Struct. Biol.

CDD: specific functional annotation with the Conserved Domain Database

Nucleic Acids Res.

Structure, function and evolution of the XPD family of iron–sulfur-containing 5′–>3′ DNA helicases

Biochem. Soc. Trans.

MMS19 links cytoplasmic iron–sulfur cluster assembly to DNA metabolism

Science

MMS19 assembles iron–sulfur proteins required for DNA metabolism and genomic integrity

Science

Telomere length regulation in mice is linked to a novel chromosome locus

Proc. Natl. Acad. Sci. U.S.A.

Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein

Cell

RTEL1 contributes to DNA replication and repair and telomere maintenance

Mol. Biol. Cell

RTEL1 is a replisome-associated helicase that promotes telomere and genome-wide replication

Science

RTEL1 maintains genomic stability by suppressing homologous recombination

Cell

Mechanism of homologous recombination: mediators and helicases take on regulatory functions

Nat. Rev. Mol. Cell Biol.

Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure

Cell

RTEL-1 enforces meiotic crossover interference and homeostasis

Science

Robust crossover assurance and regulated interhomolog access maintain meiotic crossover number

Science

Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation

Cell

A topological mechanism for TRF2-enhanced strand invasion

Review
RTEL1: functions of a disease-associated helicase