Genomic DNA transposition induced by human PGBD5

Henssen, Anton; Hénaff, Elizabeth; Jiang, Eileen; Eisenberg, Amy; Carson, Julianne; Villasante, Camila M.; Ray, Mondira; Still, Eric; Burns, Melissa; Gandara, Jorge; Feschotte, Cédric; Mason, Christopher E.; Kentsis, Alex

doi:10.1101/023887

Cited by 9 publications

(31 citation statements)

References 54 publications

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“…2A). Consistent with the notion that tolerance of PGBD5 DNA nuclease activity requires active DNA repair in cells, mutation of the aspartate catalytic triad (D168A, D194A, D386A) thought to catalyze phosphodiester bond hydrolysis during transposase-induced DNA rearrangements (16), completely abrogated the enhanced susceptibility of RPE cells upon PGBD5 expression ( Fig. 2B).…”

Section: Pgbd5 Expression Is Sufficient To Confer Susceptibility To Isupporting

confidence: 83%

“…Missense GFP-PGBD5 mutants were generated using site-directed mutagenesis according to the manufacturer's instructions (QuikChange Lightning, Agilent, Santa Clara, CA, USA) as described (16). Doxycycline-inducible pINDUCER21 vector was obtained from Thomas Westbrook (57), and used to generate pINDUCER21-PGBD5 using Gateway cloning, according to the manufacturer's instructions (Fisher Scientific, Watham, MA, USA).…”

Section: Plasmid Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Recently, the human piggyBac transposable element derived 5 (PGBD5) was identified as an active DNA transposase that is able to mobilize synthetic DNA transposons in human cells (16). PGBD5-mediated DNA transposition requires the DDD catalytic triad in the PGBD5 transposase domain and specific DNA recognition sequences and target sites (16). In particular, PGBD5 was found to be expressed in the majority of childhood solid tumors, including refractory rhabdoid tumors, where it promotes site-specific genomic rearrangements and mutations of tumor suppressor genes at least in part due to the aberrant targeting of its DNA nuclease activity (17).…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Henssen¹,

Reed

Jiang³

et al. 2017

Preprint

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Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory.Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have now found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5 that can promote site-specific genomic rearrangements in human cells.Using functional genetic approaches, we found that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce hypersensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment, and underwent apoptosis in both dividing and G1 phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro.Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including significant anti-tumor activity against patientderived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.peer-reviewed)

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Section: Pgbd5 Expression Is Sufficient To Confer Susceptibility To Isupporting

confidence: 83%

Section: Plasmid Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Henssen¹,

Reed

Jiang³

et al. 2017

Preprint

Self Cite

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“…In sum, these examples show that 4Tran-PCR is capable of detecting differences in TE integration sites that are present in a population of cells. While other techniques have been developed solely focused on detecting new TE integrations [55,56], a more comparative analysis is needed to assess the performance of this aspect of 4Tran-PCR.…”

Section: Tran-pcr Detects Te Insertion Polymorphismsmentioning

confidence: 99%

The impact of endogenous retroviruses on nuclear organization and gene expression

Raviram

et al. 2018

Preprint

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Background: The organization of chromatin in the nucleus plays an essential role in gene regulation. When considering the mammalian genome it is important to take into account that about half of the DNA is comprised of transposable elements. Given their repetitive nature, reads associated with these elements are generally discarded or randomly distributed among elements of the same type in genome-wide analyses. Thus, it is challenging to identify the activities and properties of individual transposons. As a result, we only have a partial understanding of how transposons contribute to chromatin folding and how they impact gene regulation.

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Why do young people get cancer?

Kentsis

2020

Pediatric Blood & Cancer

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Oncologists and cancer biologists are frequently confronted by the question of what causes cancer? This is particularly vexing for cancers affecting children and young adults who have had limited exposure to environmental mutagens and the effects of aging. Here, I focus on a general framework of the causes of early-onset cancer development in children and young adults by relating inherited and constitutional cancer predisposition, oncogenic pathogens, and developmental mutations. This framework has implications not only for mechanistic investigation of young cancers, but should also clarify improved strategies for their treatment, screening, and potential prevention. K E Y W O R D Soncogenes, oncology, pediatric hematology/oncology, tumor biology

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Genomic DNA transposition induced by human PGBD5

Cited by 9 publications

References 54 publications

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

The impact of endogenous retroviruses on nuclear organization and gene expression

Why do young people get cancer?

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