RECQL4 and p53 potentiate the activity of polymerase γ and maintain the integrity of the human mitochondrial genome

Gupta, Shruti; De, Siddharth; Srivastava, Vivek; Hussain, Mansoor; Kumari, Jaya; Muniyappa, K.; Sengupta, Sagar

doi:10.1093/carcin/bgt315

Cited by 57 publications

(61 citation statements)

References 48 publications

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“…RECQL4, a member of RECQ helicase family with DNAunwinding activity (7), plays an important role in maintaining the stability of nuclear (8) and mitochondrial genomes (9)(10)(11). This is well supported by the existence of three human autosomal recessive disorders Rothmund-Thomson syndrome (RTS; ref.…”

Section: Introductionmentioning

confidence: 99%

Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT–YB1–MDR1 Signaling Pathway

Fang

Niu

et al. 2016

Cancer Research

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Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatinresistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT-YB1-MDR1 axis to improve gastric cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT–YB1–MDR1 Signaling Pathway

Fang

Niu

et al. 2016

Cancer Research

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“…Recent studies suggest additional functions of RecQL4, e.g. for maintaining the integrity of telomeres and the mitochondrial genome (22–27). …”

Section: Introductionmentioning

confidence: 99%

The intrinsically disordered amino-terminal region of human RecQL4: multiple DNA-binding domains confer annealing, strand exchange and G4 DNA binding

Keller¹,

Kiosze²,

Sachsenweger³

et al. 2014

Nucleic Acids Research

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Human RecQL4 belongs to the ubiquitous RecQ helicase family. Its N-terminal region represents the only homologue of the essential DNA replication initiation factor Sld2 of Saccharomyces cerevisiae, and also participates in the vertebrate initiation of DNA replication. Here, we utilized a random screen to identify N-terminal fragments of human RecQL4 that could be stably expressed in and purified from Escherichia coli. Biophysical characterization of these fragments revealed that the Sld2 homologous RecQL4 N-terminal domain carries large intrinsically disordered regions. The N-terminal fragments were sufficient for the strong annealing activity of RecQL4. Moreover, this activity appeared to be the basis for an ATP-independent strand exchange activity. Both activities relied on multiple DNA-binding sites with affinities to single-stranded, double-stranded and Y-structured DNA. Finally, we found a remarkable affinity of the N-terminus for guanine quadruplex (G4) DNA, exceeding the affinities for other DNA structures by at least 60-fold. Together, these findings suggest that the DNA interactions mediated by the N-terminal region of human RecQL4 represent a central function at the replication fork. The presented data may also provide a mechanistic explanation for the role of elements with a G4-forming propensity identified in the vicinity of vertebrate origins of DNA replication.

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“…Our recent results (De et al, 2012;Gupta et al, 2014) led to the question whether the lack of mitochondrial localization of RECQL4 in RTS patients affects the functioning of the mitochondria and, thereby, contributes to the neoplastic transformation process. To answer this question, two cellular models were employed: (i) hTERT immortalized normal human fibroblasts GM07532 and RTS patient fibroblast cell lines AG03587, AG05013, AG05139, L9552914-J, B1865425K, D8903644-K; (ii) an isogenic system, wherein either Aequorea coerulescens (Ac)GFP-tagged wild-type RECQL4 or RECQL4 without the mitochondrial localization signal, i.e.…”

Section: Results and Discussion Lack Of Localization Of Recql4 To Mitmentioning

confidence: 99%

“…RECQL4 is involved in enhancing the processivity and polymerization of mitochondrial DNA (mtDNA) replication. Hence, absence of RECQL4 contributes to multiple mutations and polymorphisms over the entire mtDNA within cells of RTS patients (Gupta et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial functions of RECQL4 are required for the prevention of aerobic glycolysis-dependent cell invasion

Kumari

Hussain

et al. 2016

Journal of Cell Science

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Germline mutations in RECQL4 helicase are associated with Rothmund-Thomson syndrome, which is characterized by a predisposition to cancer. RECQL4 localizes to the mitochondria, where it acts as an accessory factor during mitochondrial DNA replication. To understand the specific mitochondrial functions of RECQL4, we created isogenic cell lines, in which the mitochondrial localization of the helicase was either retained or abolished. The mitochondrial integrity was affected due to the absence of RECQL4 in mitochondria, leading to a decrease in F 1 F 0 -ATP synthase activity. In cells where RECQL4 does not localize to mitochondria, the membrane potential was decreased, whereas ROS levels increased due to the presence of high levels of catalytically inactive SOD2. Inactive SOD2 accumulated owing to diminished SIRT3 activity. Lack of the mitochondrial functions of RECQL4 led to aerobic glycolysis that, in turn, led to an increased invasive capability within these cells. Together, this study demonstrates for the first time that, owing to its mitochondrial functions, the accessory mitochondrial replication helicase RECQL4 prevents the invasive step in the neoplastic transformation process.

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RECQL4 and p53 potentiate the activity of polymerase γ and maintain the integrity of the human mitochondrial genome

Abstract: The biochemical mechanisms by which RECQL4 and p53 affect mtDNA replication have been elucidated. Resequencing of RTS and LFS patients' mitochondrial genome reveals common mutations indicating similar mechanisms of regulation by RECQL4 and p53.

Cited by 57 publications

References 48 publications

Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT–YB1–MDR1 Signaling Pathway

Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT–YB1–MDR1 Signaling Pathway

The intrinsically disordered amino-terminal region of human RecQL4: multiple DNA-binding domains confer annealing, strand exchange and G4 DNA binding

Mitochondrial functions of RECQL4 are required for the prevention of aerobic glycolysis-dependent cell invasion

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