Impaired p32 Regulation Caused by the Lymphoma-Prone RECQ4 Mutation Drives Mitochondrial Dysfunction

Wang, Jiin-Tarng; Xu, Xinlin; Alontaga, Aileen Y.; Chen, Yuan; Liu, Yilun

doi:10.1016/j.celrep.2014.03.037

Cited by 27 publications

(54 citation statements)

References 40 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: 84%

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: 84%

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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“…RECQL4 is related to the yeast replication factor Sld2 and is thought to be able to bind Holliday junctions and G-quadruplex DNA as well as possess DNA annealing activity [152][153][154][155]. RECQL4 levels slightly affect mtDNA copy number and a weak interaction between RECQL4 and TWINKLE has been reported in human whole-cell extracts [156,157]. However, although mutations in RECQL4 are associated with a number of disorders, none have yet been linked to defects in mtDNA replication/maintenance [158,159].…”

Section: Recql4 Helicasementioning

confidence: 99%

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

Peter

Falkenberg

2020

Genes

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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.

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“…For example, a RECQL4 cancer-inducing mutation resulting in deletion of Ala420-Ala463 disrupts RECQL4’s interaction with a mitochondrial protein, p32, known to regulate protein localization to the mitochondria. This induces a super-enrichment of RECQL4 in mitochondria and abnormally elevated mtDNA synthesis [176]. Very recent studies from the Sengupta lab provide evidence that when RECQL4 fails to properly localize to mitochondria of human cells, mitochondrial integrity is negatively affected along with a decrease in ATP synthase activity, reduction in membrane potential, and elevated ROS due to superoxide dismutase (SOD) inactivation by a SIRT3-dependent mechanism [177].…”

Section: Dna Helicases and The Metabolism Of Mitochondrial Oxidativelmentioning

confidence: 99%

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

Crouch

Brosh

2017

Free Radical Biology and Medicine

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Cells are under constant assault from reactive oxygen species that occur endogenously or arise from environmental agents. An important consequence of such stress is the generation of oxidatively damaged DNA, which is represented by a wide range of non-helix distorting and helix-distorting bulkier lesions that potentially affect a number of pathways including replication and transcription; consequently DNA damage tolerance and repair pathways are elicited to help cells cope with the lesions. The cellular consequences and metabolism of oxidatively damaged DNA can be quite complex with a number of DNA metabolic proteins and pathways involved. Many of the responses to oxidative stress involve a specialized class of enzymes known as helicases, the topic of this review. Helicases are molecular motors that convert the energy of nucleoside triphosphate hydrolysis to unwinding of structured polynucleic acids. Helicases by their very nature play fundamentally important roles in DNA metabolism and are implicated in processes that suppress chromosomal instability, genetic disease, cancer, and aging. We will discuss the roles of helicases in response to nuclear and mitochondrial oxidative stress and how this important class of enzymes help cells cope with oxidatively generated DNA damage through their functions in the replication stress response, DNA repair, and transcriptional regulation.

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Impaired p32 Regulation Caused by the Lymphoma-Prone RECQ4 Mutation Drives Mitochondrial Dysfunction

Cited by 27 publications

References 40 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

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

Mechanistic and biological considerations of oxidatively damaged DNA for helicase-dependent pathways of nucleic acid metabolism

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