Impaired elimination of DNA double-strand break-containing lymphocytes in ataxia telangiectasia and Nijmegen breakage syndrome

Porcedda, Paola; Turinetto, Valentina; Lantelme, Erica; Fontanella, Enrico; Chrzanowska, Krystyna; Ragona, Riccardo; Marchi, Mario; Delia, Domenico; Giachino, Claudia

doi:10.1016/j.dnarep.2006.05.002

Cited by 45 publications

(40 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 C and D). The dynamics of foci disassembly in the cells without and with the HAC was identical to that observed in cultured lymphocytes from patients with NBS and normal individuals, correspondingly (31). Thus, these results indicate a higher rate of rejoining of DSBs in GM07166 cells bearing alphoid tetO -HAC/NBS1.…”

Section: Conversion Of Nbs1-and Vhl-yacs Into Bacs With a Loxp Cassetsupporting

confidence: 64%

Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

Kim¹,

Кононенко²,

Erliandri³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

135

View full text Add to dashboard Cite

Human artificial chromosome (HAC)-based vectors offer a promising system for delivery and expression of full-length human genes of any size. HACs avoid the limited cloning capacity, lack of copy number control, and insertional mutagenesis caused by integration into host chromosomes that plague viral vectors. We previously described a synthetic HAC that can be easily eliminated from cell populations by inactivation of its conditional kinetochore. Here, we demonstrate the utility of this HAC, which has a unique gene acceptor site, for delivery of full-length genes and correction of genetic deficiencies in human cells. A battery of functional tests was performed to demonstrate expression of NBS1 and VHL genes from the HAC at physiological levels. We also show that phenotypes arising from stable gene expression can be reversed when cells are "cured" of the HAC by inactivating its kinetochore in proliferating cell populations, a feature that provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This generation of human artificial chromosomes should be suitable for studies of gene function and therapeutic applications.

show abstract

Section: Conversion Of Nbs1-and Vhl-yacs Into Bacs With a Loxp Cassetsupporting

confidence: 64%

Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

Kim¹,

Кононенко²,

Erliandri³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

135

View full text Add to dashboard Cite

show abstract

“…17 Although it is well known that DNA repair defects can potentiate cellular chemosensitivity to (unrepaired) oxidative damage, 82 it is less appreciated that repair deficiencies may also impair apoptosis [83][84][85][86] -presumably through failure to sense damage-thereby, exaggerating tolerance of unrepaired damage with consequent acceleration of carcinogenesis or tumor progression due to increased genetic instability. [87][88][89] Similar to most studies using systems biology, our conclusions are limited by their inferential and indirect nature, though we note that clinical observations of GK overexpression in human tumors are consistent with the model proposed. 12 It is not our contention that GKs are the same as oncogenes, as important differences can also be identified using our approach; for example, we have documented a significantly higher frequency of gene duplicates for POs than for GKs (data not shown).…”

Section: Discussionsupporting

confidence: 79%

Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

Zhao

Epstein

2011

J Hum Genet

View full text Add to dashboard Cite

Familial tumor suppressor genes comprise two subgroups: caretaker genes (CTs) that repair DNA, and gatekeeper genes (GKs) that trigger cell death. Since GKs may also induce cell cycle delay and thus enhance cell survival by facilitating DNA repair, we hypothesized that the prosurvival phenotype of GKs could be selected during cancer progression, and we used a multivariable systems biology approach to test this. We performed multidimensional data analysis, non-negative matrix factorization and logistic regression to compare the features of GKs with those of their putative antagonists, the proto-oncogenes (POs), as well as with control groups of CTs and functionally unrelated congenital heart disease genes (HDs). GKs and POs closely resemble each other, but not CTs or HDs, in terms of gene structure (Po0.001), expression level and breadth (Po0.01), DNA methylation signature (Po0.001) and evolutionary rate (Po0.001). The similar selection pressures and epigenetic trajectories of GKs and POs so implied suggest a common functional attribute that is strongly negatively selected-that is, a shared phenotype that enhances cell survival. The counterintuitive finding of similar evolutionary pressures affecting GKs and POs raises an intriguing possibility: namely, that cancer microevolution is accelerated by an epistatic cascade in which upstream suppressor gene defects subvert the normal bifunctionality of wild-type GKs by constitutively shifting the phenotype away from apoptosis towards survival. If correct, this interpretation would explain the hitherto unexplained phenomenon of frequent wild-type GK (for example, p53) overexpression in tumors.

show abstract

“…employed as positive control in genotoxicity assessment (Hashimoto et al, 2010;Porcedda et al, 2006;Sanchez-Flores et al, 2015). In a previous study with primary rat neurons, it was reported that cells remained alive and intact after 48 h of 0.1 mg/ml Act-D treatment (Martin et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Comparative study of human neuronal and glial cell sensitivity for in vitro neurogenotoxicity testing

Laffón

Fernández-Bertólez

Costa

et al. 2017

Food and Chemical Toxicology

View full text Add to dashboard Cite

a b s t r a c tCell cultures from neuronal and glial origin have proven to be powerful tools for elucidating cellular and molecular mechanisms of nervous system development and physiology, and as neurotoxicity models to evaluate in vitro the possible effects of chemicals. But cellular heterogeneity of nervous system is considerable and these cells have been shown to respond diversely to neurotoxic insults, leading to disparate results from different studies. To shed more light on suitability of cellular models of nervous origin for neurotoxicity screening, the objective of this study was to compare the sensitivity to genetic damage induction of two nervous cell lines. To this aim, neurons (SH-SY5Y) and glial (A172) cells were treated with differently-acting genotoxic agents (bleomycin, actinomycin-D, methyl methanesulfonate, mitomycin C, and griseofulvin). After discarding cytotoxicity, genotoxicity was evaluated by a battery of assays encompassing detection of different genetic lesions. Results obtained showed that glial cells are generally more resistant to genotoxic damage induced by clastogenic agents, but more sensitive to aneugenic effects. These results highlight the need of proper design of in vitro neurotoxicology studies, especially for neurogenotoxicity screening, emphasizing the importance of employing more than one nervous cell type for testing the potential toxicity of a particular exposure.

show abstract

Impaired elimination of DNA double-strand break-containing lymphocytes in ataxia telangiectasia and Nijmegen breakage syndrome

Cited by 45 publications

References 58 publications

Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

Human artificial chromosome (HAC) vector with a conditional centromere for correction of genetic deficiencies in human cells

Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology

Comparative study of human neuronal and glial cell sensitivity for in vitro neurogenotoxicity testing

Contact Info

Product

Resources

About