Human RECQ helicases: Roles in DNA metabolism, mutagenesis and cancer biology

doi:10.1016/j.semcancer.2010.10.002

Seminars in Cancer Biology

Volume 20, Issue 5, October 2010, Pages 329-339

https://doi.org/10.1016/j.semcancer.2010.10.002 Get rights and content

Abstract

Helicases use the energy of ATP hydrolysis to separate double-stranded nucleic acids to facilitate essential processes such as replication, recombination, transcription and repair. This article focuses on the human RECQ helicase gene and protein family. Loss of function of three different members has been shown to cause Bloom syndrome (BS), Werner syndrome (WS) and Rothmund–Thomson syndrome (RTS). This article outlines clinical and cellular features of these cancer predisposition syndromes, and discusses their pathogenesis in light of our understanding of RECQ helicase biochemical activities and in vivo functions. I also discuss the emerging role for RECQ helicases as predictors of disease risk and the response to therapy.

Section snippets

Prologue

Homer's Odyssey is a beguiling work, a bookend—literally—to Western literature together with the Illiad. The Odyssey is a literal and metaphorical travelogue, the forced decadal wanderings of Odysseus following the end of the Trojan war. Voyaging, wandering and sailing are recurrent themes in the Odyssey, and have served ever since as powerful metaphors for life's journey and all attempts to explore and to wrest meaning from the unknown. The muse in the following story is Nature; our goal is

Conflicts of Interest

R.J.M., Jr. has no relevant conflicts of interest to declare.

Acknowledgements

Work in the author's laboratory has been supported by grants from the NIA, NCI and the Nippon Boehringer Ingelheim Virtual Research Institute of Aging. The author is grateful to lab members who have contributed many ideas and the hard work that made this review possible. This article is dedicated to three pioneers I have had the good fortune to know as mentors and colleagues: George Martin and Arno Motulsky, who first brought Werner syndrome to my—and many others’—attention; and Larry Loeb, a

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The Bloom syndrome complex is a DNA damage repair machine. It consists of several protein components which are functional in isolation, but interdependent in cells for the maintenance of accurate homologous recombination. Mutations to any of the genes encoding these proteins cause numerous physical and developmental markers as well as phenotypes of genome instability, infertility, and cancer predisposition. Here we review the published structural and biochemical data on each of the components of the complex: the helicase BLM, the type IA topoisomerase TOP3A, and the OB-fold-containing RMI and RPA subunits. We describe how each component contributes to function, interacts with each other, and the DNA that it manipulates/repairs.
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Citation Excerpt :
These results indicated that decreased expression of RECQL5 could enhance DDP sensitivity in NSCLC. RECQL5 is the last member of the RECQ helicase family, and it exerts regulatory roles in maintain genome stability and homologous recombination of genome, indicating RECQL5 may play the similar role in tumorigenesis or cancer susceptibility like other members of RECQ helicase family [23]. In the present study, by analyzing the publicly available database TCGA, we found that RECQL5 was upregulated in NSCLC tissues and the high abundance of RECQL5 could predict poor survival rate of LUAD patients, indicating the potential involvement of RECQL5 in NSCLC prognosis (Fig. 1A and B).
Non-small cell lung cancer (NSCLC) patients have a lower 5-year survival rate, and the distant tumor metastasis and drug resistance are the main reasons for the high mortality. RECQL5, a member of RecQ helicases family, has been linked to tumorigenesis of various cancers expect NSCLC. In the current study, analysis with the Cancer Genome Atlas (TCGA) dataset showed that the level of RECQL5 was elevated in LUAD (Lung Adenocarcinoma) and LUSC (lung squamous carcinomas), two major subtypes of NSCLC, which was confirmed by immunohistochemistry staining on Tissue array slides. The level of RECQL5 was also elevated in NSCLC cell lines. Further, Kaplan-Meier analysis of TCGA dataset suggested that the up-regulated RECQL5 was associated with poor prognosis of LUAD, but not with that of LUSC. Knockdown of RECQL5 significantly inhibited the invasion and migration of NSCLC cells, and suppressed epithelial-mesenchymal transition (EMT) as indicated by the changes of EMT-related proteins, while overexpression of RECQL5 displayed reverse effects. Lung metastasis was also suppressed by RECQL5 knockdown. Additionally, the addition of Akt inhibitor LY294002 reversed the effects of RECQL5 overexpression on cell migration, invasion and EMT. Moreover, knockdown of RECQL5 increased the apoptosis of cisplatin-resistant A549 cell line (A549/DDP) caused by cisplatin treatment. In summary, RECQL5 contributed to the metastasis of NSCLC and assisted NSCLC cells incompletely response to cisplatin therapy, and could be considered as a biomarker or clinical target for NSCLC.
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Overexpression of the MYC oncogene is a molecular hallmark of both cancer initiation and progression. Targeting MYC is a logical and effective cancer therapeutic strategy. A special DNA secondary structure, the G-quadruplex (G4), is formed within the nuclease hypersensitivity element III₁ (NHE III₁) region, located upstream of the MYC gene's P1 promoter that drives the majority of its transcription. Targeting such G4 structures has been a focus of anticancer therapies in recent decades. Thus, a comprehensive review of the MYC G4 structure and its role as a potential therapeutic target is timely. In this review, we first outline the discovery of the MYC G4 structure and evidence of its formation in vitro and in cells. Then, we describe the functional role of G4 in regulating MYC gene expression. We also summarize three types of MYC G4-interacting proteins that can promote, stabilize and unwind G4 structures. Finally, we discuss G4-binding molecules and the anticancer activities of G4-stabilizing ligands, including small molecular compounds and peptides, and assess their potential as novel anticancer therapeutics.
Mining the role of RECQL5 in gastric cancer and seeking potential regulatory network by bioinformatics analysis
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The role of RecQ protein-like 5 (RECQL5) in gastric carcinoma (GC) is still unclear. Here, we investigated the role of RECQL5 in human GC and its potential regulatory network via bioinformatics analysis.
Bioinformatic analysis was performed using data in the Oncomine database, Kaplan- Meier Plotter online software, MethHC database, catalogue of somatic mutations in cancer (COSMIC), cbioportal database and String database. Then, we verified the association between RECQL5 expression and GC prognosis by immunohistochemistry (IHC). The independent prognostic factors were determined by Cox multivariate analysis.
It was found that both the mRNA and protein expression levels of RECQL5 were downregulated in GC samples (P < .05). Low RECQL5 expression indicated a poor prognosis in GC patients and is the independent prognostic factors for GC. No correlation between RECQL5 mRNA and DNA methylation was found using the MethHC database. The analysis of the COSMIC database showed a high proportion of missense mutation in GC. The functional enrichment analysis predicted that RECQL5 plays a role in DNA repair and cellular responses to DNA damage stimulus. RECQL5 might be enriched in homologous recombination pathways and Fanconi anemia pathway. Bioinformatics analysis identified 5 genes, namely POLR2D, POLR2G, DXO, KIN, and EIF2D, that were significantly correlated with RECQL5.
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Citation Excerpt :
Notably, the telomere damage in the nucleus can trigger the activation of p53 that is associated with mitochondrial dysfunction, causing apoptosis and age-related dysfunction of the mitochondrion-rich quiescent tissues [27,28]. The most striking example that supports the somatic mutation theory is seen in patients suffering from inherited DNA repair deficits, who exhibit premature ageing-like phenotypes called Werner syndrome (WS or WRN) [29,30]. They have mutations through which the WRN gene product is lost, resulting in early onset cataracts, scleroderma, thinning grey hair, atherosclerosis, diabetes, myocardial infarction, stroke, osteoporosis, and cancers [29,31].
With the rapid advancement of sequencing technologies over the last two decades, it is becoming feasible to detect rare variants from somatic tissue samples. Studying such somatic mutations can provide deep insights into various senescence-related diseases, including cancer, inflammation, and sporadic psychiatric disorders. While it is still a difficult task to identify true somatic mutations, relentless efforts to combine experimental and computational methods have made it possible to obtain reliable data. Furthermore, state-of-the-art machine learning approaches have drastically improved the efficiency and sensitivity of these methods. Meanwhile, we can regard somatic mutations as a counterpart of germline mutations, and it is possible to apply well-formulated mathematical frameworks developed for population genetics and molecular evolution to analyze this ‘somatic evolution’. For example, retrospective cell lineage tracing is a promising technique to elucidate the mechanism of pre-diseases using single-cell RNA-sequencing (scRNA-seq) data.

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ReviewHuman RECQ helicases: Roles in DNA metabolism, mutagenesis and cancer biology

Abstract

Section snippets

Prologue

Conflicts of Interest

Acknowledgements

Biophys Chem

Cytogenet Cell Genet

Mech Ageing Dev

Cell

Exp Gerontol

Genomics

J Biol Chem

DNA Repair

DNA Repair

Lancet

DNA Repair

Am J Hum Genet

DNA Repair

J Biol Chem

DNA Repair

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

DNA Repair

J Biol Chem

J Biol Chem

J Biol Chem

DNA Repair

DNA Repair

Mol Cell

Mut Res/Rev Mut Res

Cell

Mech Ageing Dev

Structure and mechanism of helicases and nucleic acid translocases

Annu Rev Biochem

Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs

Am J Dis Child

Bloom syndrome: a Mendelian prototype of somatic mutational disease

Medicine

Bloom's syndrome. VIII. Review of clinical and genetic aspects

Werner's syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process

Medicine

Werner's sydrome: an underdiagnosed disorder resembling premature aging

Age

Excess of rare cancers in Werner syndrome (adult progeria)

Cancer Epidemiol Biomarkers Prev

Cancer pathogenesis in the human RecQ helicase deficiency syndromes

Werner syndrome

The spectrum of WRN mutations in Werner syndrome patients

Human Mutat

Ueber cataracten in verbindung mit einer eigentümlichen hautdegenera-tion

Arch Klin Exp Ophtal

Poikiloderma congenitale

Br J Dermatol

Rothmund's syndrome–Thomson's syndrome: congenital poikiloderma with and without juvenile cataracts. A review of the literature, report of a case, and discussion of the relationship of the two syndromes

AMA Arch Dermatol

Clinical manifestations in a cohort of 41 Rothmund–Thomson syndrome patients

Am J Hum Genet

The mutation spectrum in RECQL4 diseases

Eur J Hum Genet

Review
Human RECQ helicases: Roles in DNA metabolism, mutagenesis and cancer biology