The role of RecQ helicases in non-homologous end-joining

Keijzers, Guido; Maynard, Scott; Shamanna, Raghavendra A.; Rasmussen, Lene Juel; Croteau, Deborah L.; Bohr, Vilhelm A.

doi:10.3109/10409238.2014.942450

Cited by 26 publications

(16 citation statements)

References 176 publications

(218 reference statements)

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“…DBSs are repaired through either homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). It has been proposed that the choice between HR and NHEJ is determined in part by heterochromatin status and the chemical nature of the DSB, and that canonical NHEJ may be preferred for exogenous DSB repair during the G 0 and G 1 phases of the cell cycle (Kakarougkas and Jeggo, 2014; Keijzers et al, 2014). WRN physically interacts with a number of players in NHEJ such as Ku70/80, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and DNA ligase IV/XRCC4 (Kusumoto-Matsuo et al, 2014; Kusumoto et al, 2008).…”

Section: Cellular Functions Of the Wrn Gene Productmentioning

confidence: 99%

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

Oshima

Sidorova

Monnat

2017

Ageing Research Reviews

200

185

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Werner syndrome (WS) is a prototypical segmental progeroid syndrome characterized by multiple features consistent with accelerated aging. It is caused by null mutations of the WRN gene, which encodes a member of the RECQ family of DNA helicases. A unique feature of the WRN helicase is the presence of an exonuclease domain in its N-terminal region. Biochemical and cell biological studies during the past decade have demonstrated involvements of the WRN protein in multiple DNA transactions, including DNA repair, recombination, replication and transcription. A role of the WRN protein in telomere maintenance could explain many of the WS phenotypes. Recent discoveries of new progeroid loci found in atypical Werner cases continue to support the concept of genomic instability as a major mechanism of biological aging. Based on these biological insights, efforts are underway to develop therapeutic interventions for WS and related progeroid syndromes.

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Section: Cellular Functions Of the Wrn Gene Productmentioning

confidence: 99%

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

Oshima

Sidorova

Monnat

2017

Ageing Research Reviews

200

185

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“…Although the WRN and the BLM helicases belong both to the family of RecQ helicases, defects of either during DSB response may lead to opposing outcomes [Suhasini and Brosh, 2013;Croteau et al, 2014;Keijzers et al, 2014;Kitano, 2014]. Loss of WRN is associated with a variegated translocation mosaicism and a reduction in DNA recombination [Salk et al, 1981;Dhillon et al, 2007;Melcher et al, 2000].…”

Section: Genes and Proteinsmentioning

confidence: 99%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

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“…Shelterin and other proteins linked to it perform several functions involving telomere homeostasis and stabilizing the telomere complex [60,63]. Many of the telomeric proteins play role in various DNA repair mechanisms such as non-homologous end joining (NHEJ), homologous recombination (HR), base excision repair (BER) and nucleotide excision repair (NER) [64][65][66]. Most of these DNA repair proteins also interact directly with the Shelterin complex.…”

Section: Telomere Homeostasis and Cancermentioning

confidence: 99%

Tolomeres and Cancer

Rk¹,

Azam²,

Khalid³

2019

J Biomol Res Ther

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Telomere protects the chromosomes in normal cells, and their shortening due to cell divisions and oxidative stress induces telomere shortening causing chromosomal instability. Telomerase is an enzyme that adds TTAGG telomeric repeats at chromosomal ends. The activity of telomerase enzyme plays a significant role in initiation and progression of cancer cells. In cancer cells the telomere length is maintained by telomerase enzyme. Cancer cells survive due to the activity of telomerase enzyme due to which the length of telomere is maintained and cell evades cell death mechanisms. In cancer cells telomere shortening or dysfunctional telomeres suppress cancer progression and development due to the activation of cellular senescence pathway. In this review we summarize telomere structure, function and the role telomere plays in cancer development and progression. Hermen J. Muller and Barbara McClintock identified telomere as a structure present at the ends of the chromosomes. The word telomere is derived from the Greek word "telos" which means ends and "meres" means part. Shorter telomere length or the complete absence of telomere induces end to end fusion of the chromosomes and ultimately cause cellular senescence or cell death. James D Watson in 1970s termed end replication problem in which during DNA replication, the DNA dependant polymerase does not replicates completely at the 5' terminal end leaving small regions of the telomere uncopied. In 1960 Leonard Hayflick and his colleagues identified that the human diploid cell can undergo limited number of cell divisions in culture. The maximum number of divisions that a cell can achieve in-vitro is known as Hayflick limit which was termed after leonard Hayflick. When the cells reaches to a limit where they can no longer divide will eventually go under biochemical and morphological changes that eventually leads to cell cycle arrest, a process known as "cellular senescence. The telomerase is an enzyme that functions to add telomere repeats to the ends of the chromosomes and was identified in 1984 by Elizbeth and her collague. The presence of telomerase enzyme activity was also identified in human cancer cell lines by Gregg in 1989. Another study conducted by Greider and associates showed the absence of telomerase enzyme in normal somatic cell. Shay and Harley in 1990s detected the presence of telomerase activity in 90 out of 101 human tumor cell samples isolated from 12 different tumor types, whereas they have found no activity in normal somatic samples (n=50) isolated from 4 different tissue types. Since then various studies on 2600 human tumor samples have shown the telomerase activity in around 90% of different tumor cells. The existence of telomerase activity in cancer cells clearly demonstrates a major role of this enzyme in cancer pathogenesis. Telomeres plays a critical role in cancer, aging, Progeria (premature aging) and various other age related disorders due to which telomere and telomerase enzyme are recently an active area of research.

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The role of RecQ helicases in non-homologous end-joining

Cited by 26 publications

References 176 publications

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Tolomeres and Cancer

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