Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability

Fukawatase, Yoshihiro; Toyoda, Masashi; Okamura, Koji; Nakamura, Ken; Nakabayashi, Kazuhiko; Takada, Shuji; Yamazaki-Inoue, Mayu; Masuda, Akira; Nasu, Michiyo; Hata, Kenichiro; Hanaoka, Kazunori; Higuchi, Akon; Takubo, Kaiyo; Umezawa, Akihiro

doi:10.1038/srep05421

Cited by 34 publications

(35 citation statements)

References 36 publications

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“…We were not able to detect any consistently up or downregulated genes or pathways in pluripotent state between A-T iPSCs and iPSCs generated from healthy donor fibroblasts (WT iPSCs). These data show that ATM deficiency does not affect global gene expression in the pluripotent state, similar to previous reports [21][22][23][24].…”

Section: Ipscs With Deficiencies In Atmsupporting

confidence: 80%

“…Mutations in ATM result in defective cell cycle checkpoint activation and a reduced capacity for repair of DNA double-strand breaks (DSBs). iPSCs from A-T patients have been generated by multiple laboratories, but the issue of genomic variation has not been comprehensively investigated [20][21][22][23][24]. We analyze the CNVs of iPSCs derived from A-T patient using high-resolution single-nucleotide polymorphism (SNP) array and discovered differential genome-wide distribution relative to replication timing organization and the effects of integrating versus nonintegrating reprogramming methods.…”

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confidence: 99%

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Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Baccei

et al. 2016

Stem Cells and Development

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Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM-deficient iPSCs relative to wild-type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral (RV) reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DDR reveals unique vulnerability of early replicating open chromatin to RV vectors.

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Section: Ipscs With Deficiencies In Atmsupporting

confidence: 80%

mentioning

confidence: 99%

Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Baccei

et al. 2016

Stem Cells and Development

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“…γ‐H2A.X recruits Mbc1 at the site of the break and triggers DNA repair by recruiting the HR repair machinery including Brca1, Brca2, Rad51, and 53BP. Supporting the central role of p53 in eliminating DNA‐damaged cells during reprogramming, MEFs deficient in either Atm or 53BP1 show a decrease in reprogramming efficiency . Moreover, HR DNA DSB repair genes such as Brca1, Brca2, and Rad51, Fanconi anemia genes involved in both DNA DSB repair and interstrand cross‐link processing, and nonhomologous end joining DSB repair genes have all been shown to be required for efficient reprogramming to a pluripotent state.…”

Section: A Functional Dissection Of the Reprogramming Processmentioning

confidence: 95%

Mechanisms underlying the formation of induced pluripotent stem cells

González

Huangfu

2015

WIREs Developmental Biology

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Human pluripotent stem cells (hPSCs) offer unique opportunities for studying human biology, modeling diseases and for therapeutic applications. The simplest approach so far to generate human PSCs lines is through reprogramming of somatic cells from an individual by defined factors, referred to simply as reprogramming. Reprogramming circumvents the ethical issues associated with human embryonic stem cells (hESCs) and nuclear transfer hESCs (nt-hESCs), and the resulting induced pluripotent stem cells (hiPSCs) retain the same basic genetic makeup as the somatic cell used for reprogramming. Since the first report of iPSCs by Takahashi and Yamanaka, the molecular mechanisms of reprogramming have been extensively investigated. A better mechanistic understanding of reprogramming is fundamental not only to iPSC biology and improving the quality of iPSCs for therapeutic use, but also to our understanding of the molecular basis of cell identity, pluripotency and plasticity. Here we summarize the genetic, epigenetic and cellular events during reprogramming, and the roles of various factors identified thus far in the reprogramming process.

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“…Medulloblastoma forms in similar phenotype and anatomical location by haploinsufficiency of ptch1 in mice, but do not exhibit loss of heterozygosity (6,7). Human disease-specific induced pluripotent stem cell (iPSC) has been used as one of human disease models to complement animal models (8,9). Basic schemes how to utilize patient iPSCs for disease mechanism studies have been well demonstrated (10,11).…”

Section: Introductionmentioning

confidence: 99%

Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1

Ikemoto

Miyashita

Nasu

et al. 2019

Preprint

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Gorlin syndrome is a rare autosomal dominant hereditary disease with high incidence of tumors such as basal cell carcinoma and medulloblastoma. Disease-specific induced pluripotent stem cells (iPSCs) have now been used as a model to analyze disease pathogenesis as well as an animal model. In this study, we generated iPSCs derived from fibroblasts of four patients with Gorlin syndrome (Gln-iPSCs) with a heterozygous mutation of the PTCH1 gene. Gln-iPSCs from the four patients developed medulloblastoma in 100% (four out of four), a manifestation of Gorlin syndrome, in the teratomas after implantation into immunodeficient mice, but none (0/584) of the other iPSC-teratomas. One of the medulloblastomas had loss of heterozygosity in the PTCH1 gene while benign teratoma, i.e. non-medulloblastoma part, did not, indicating a close clinical correlation between tumorigenesis in Gorlin syndrome patients and Gln-iPSCs.

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Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability

Cited by 34 publications

References 36 publications

Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Influence ofATM-Mediated DNA Damage Response on Genomic Variation in Human Induced Pluripotent Stem Cells

Mechanisms underlying the formation of induced pluripotent stem cells

Gorlin syndrome-induced pluripotent stem cells form medulloblastoma with loss of heterozygosity in PTCH1

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