Transient ALT activation protects human primary cells from chromosome instability induced by low chronic oxidative stress

dc.contributor.authorColuzzi, Elisaen
dc.contributor.authorBuonsante, Rossellaen
dc.contributor.authorLeone, Stefanoen
dc.contributor.authorAsmar, Anthony J.en
dc.contributor.authorMiller, Kelley L.en
dc.contributor.authorCimini, Danielaen
dc.contributor.authorSgura, Antonellaen
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2019-01-09T17:29:48Zen
dc.date.available2019-01-09T17:29:48Zen
dc.date.issued2017-02-27en
dc.description.abstractCells are often subjected to the effect of reactive oxygen species (ROS) as a result of both intracellular metabolism and exposure to exogenous factors. ROS-dependent oxidative stress can induce 8-oxodG within the GGG triplet found in the G-rich human telomeric sequence (TTAGGG), making telomeres highly susceptible to ROS-induced oxidative damage. Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes and their dysfunction is believed to affect a wide range of cellular and/or organismal processes. Acute oxidative stress was shown to affect telomere integrity, but how prolonged low level oxidative stress, which may be more physiologically relevant, affects telomeres is still poorly investigated. Here, we explored this issue by chronically exposing human primary fibroblasts to a low dose of hydrogen peroxide. We observed fluctuating changes in telomere length and fluctuations in the rates of chromosome instability phenotypes, such that when telomeres shortened, chromosome instability increased and when telomeres lengthened, chromosome instability decreased. We found that telomere length fluctuation is associated with transient activation of an alternative lengthening of telomere (ALT) pathway, but found no evidence of cell death, impaired proliferation, or cell cycle arrest, suggesting that ALT activation may prevent oxidative damage from reaching levels that threaten cell survival.en
dc.description.notesWe would like to thank Brent Bowden (Virginia Tech), Bin He (Virginia Tech), and Francesco Berardinelli (University Roma Tre) for technical assistance and all the members of the Cimini and Sgura labs for useful discussions and feedback. We would also like to acknowledge DAKO for generously supplying the chromosome 2 centromeric PNA probe. Work in the Cimini lab supported by HFSP grant RGY0069/2010 and NSF grants MCB-0842551 and MCB-1517506.en
dc.description.sponsorshipHFSP [RGY0069/2010]; NSF [MCB-0842551, MCB-1517506]en
dc.format.extent12en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/srep43309en
dc.identifier.issn2045-2322en
dc.identifier.other43309en
dc.identifier.pmid28240303en
dc.identifier.urihttp://hdl.handle.net/10919/86650en
dc.identifier.volume7en
dc.language.isoen_USen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectin-situ hybridizationen
dc.subjectrepeat amplification protocolen
dc.subjectdna-damageen
dc.subjecttelomere maintenanceen
dc.subjecthuman fibroblastsen
dc.subjectrecombinationen
dc.subjectmechanismsen
dc.subjectquantificationen
dc.subjectaccumulationen
dc.subjectmicronucleusen
dc.titleTransient ALT activation protects human primary cells from chromosome instability induced by low chronic oxidative stressen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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