Elevated presence of retrotransposons at sites of DNA double strand break repair in mouse models of metabolic oxidative stress and MYC-induced lymphoma

Rockwood, Lynne D; Felix, Klaus; Janz, Siegfried

doi:10.1016/j.mrfmmm.2004.01.005

Cited by 25 publications

(21 citation statements)

References 31 publications

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“…Yeast, mammalian, fungal, and plant retrotransposons can be activated by oxidative stress and/or DNA damage (10,(43)(44)(45)(46)(47). Oxidative stress and DNA damage are associated with aging in a variety of organisms (19).…”

Section: Discussionmentioning

confidence: 99%

“…Retromobility refers to integration of cDNA at new sites as well as recombination events between cDNA and preexisting genomic retrotransposon sequences. In addition to acting as insertional mutagens, retrotransposons are frequently present at the sites of chromosome rearrangements, because DNA repair processes can capture and insert cDNA into the genome at sites of damage (4)(5)(6)(7)(8)(9)(10)(11). Additionally, retrotransposons can produce reverse transcripts of cellular mRNA that are incorporated into genomes as processed pseudogenes (12,13).…”

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confidence: 99%

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Retrotransposition is associated with genome instability during chronological aging

Maxwell

Burhans

Curcio

2011

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

131

119

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Genetic damage through mutations and genome rearrangements has been hypothesized to contribute to aging. The specific mechanisms responsible for age-induced increases in mutation and chromosome rearrangement frequencies and a potential causative role for DNA damage in aging are under active investigation. Retrotransposons are mobile genetic elements that cause insertion mutations and contribute to genome rearrangements through nonallelic recombination events in humans and other organisms. We have investigated the role of endogenous Ty1 retrotransposons in aging-associated increases in genome instability using the Saccharomyces cerevisiae chronological aging model. We show that ageinduced increases in loss of heterozygosity and chromosome loss events are consistently diminished by mutations or treatments that reduce Ty1 retrotransposition. Ty1 mobility is elevated in very old yeast populations, and new retromobility events are often associated with chromosome rearrangements. These results reveal a correlation between retrotransposition and genome instability during yeast aging. Retrotransposition may contribute to genetic damage during aging in diverse organisms and provides a useful tool for studying whether genetic damage is a causative factor for aging.long-terminal repeat retrotransposon | mobile element | chromosomal rearrangement | lifespan

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Retrotransposition is associated with genome instability during chronological aging

Maxwell

Burhans

Curcio

2011

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

131

119

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“…Furthermore, doublestrand breaks in chromosomal L1 elements can be repaired by homologous recombination with nonallelic endogenous elements, leading in some instances to gene conversion between repetitive elements (51). Increased prevalence of L1 retrotransposon sequences at sites of DNA double-strand break repair in mouse models of metabolic oxidative stress and MYC-induced lymphoma suggests a role for L1 in DNA rearrangements (52). In addition, involvement of L1-encoded products in AluI transposition has been recently shown (24,25), suggesting that activation of L1 by genotoxic mutagens may also contribute to chromosomal rearrangements by transposing AluI sequences.…”

Section: Discussionmentioning

confidence: 99%

Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

Stribinskis

Ramos

2006

Cancer Research

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Long interspersed nuclear elements [LINE-1 (L1)] are abundant retrotransposons in mammalian genomes that remain silent under most conditions. Cellular stress signals activate L1, but the molecular mechanisms controlling L1 activation remain unclear. Evidence is presented here that benzo(a) pyrene (BaP), an environmental hydrocarbon metabolized by mammalian cytochrome P450s to reactive carcinogenic intermediates, increases L1 retrotransposition in HeLa cells. Increased retrotransposition is mediated by up-regulation of L1 RNA levels, increased L1 cDNA synthesis, and stable genomic integration. Activation of L1 is dependent on the ability of BaP to cause DNA damage because it is absent in HeLa cells challenged with nongenotoxic hydrocarbon carcinogens. Thus, the mutations and genomic instability observed in human populations exposed to genotoxic environmental hydrocarbons may involve epigenetic activation of mobile elements dispersed throughout the human genome.

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“…Some retrotransposons, such as the mammalian L1 element and yeast Ty1 element, are frequently present at sites of chromosome rearrangements and can produce retrotransposed copies of gene transcripts (Derr et al 1991;Esnault et al 2000;Dunham et al 2002;Gilbert et al 2002;Umezu et al 2002;Abeysinghe et al 2003;Maxwell and Curcio 2007;Robberecht et al 2013). Furthermore, mammalian L1 elements and yeast Ty1 elements are both activated by increased reactive oxygen species (ROS) and DNA damage (Rockwood et al 2004;Beauregard et al 2008;Stoycheva et al 2010;Giorgi et al 2011), which are stresses associated with aging (Burhans and Weinberger 2012;Kirkwood and Kowald 2012). However, the potential role of retrotransposons and the genome instability they cause in aging has not yet been well investigated.…”

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confidence: 99%

Extension of Saccharomyces paradoxus Chronological Lifespan by Retrotransposons in Certain Media Conditions Is Associated with Changes in Reactive Oxygen Species

VanHoute

Maxwell

2014

Genetics

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Retrotransposons are mobile DNA elements present throughout eukaryotic genomes that can cause mutations and genome rearrangements when they replicate through reverse transcription. Increased expression and/or mobility of retrotransposons has been correlated with aging in yeast, Caenorhabditis elegans, Drosophila melanogaster, and mammals. The many copies of retrotransposons in humans and various model organisms complicate further pursuit of this relationship. The Saccharomyces cerevisiae Ty1 retrotransposon was introduced into a strain of S. paradoxus that completely lacks retrotransposons to compare chronological lifespans (CLSs) of yeast strains with zero, low, or high Ty1 copy number. Yeast chronological lifespan reflects the progressive loss of cell viability in a nondividing state. Chronological lifespans for the strains were not different in rich medium, but were extended in high Ty1 copy-number strains in synthetic medium and in rich medium containing a low dose of hydroxyurea (HU), an agent that depletes deoxynucleoside triphosphates. Lifespan extension was not strongly correlated with Ty1 mobility or mutation rates for a representative gene. Buffering deoxynucleoside triphosphate levels with threonine supplementation did not substantially affect this lifespan extension, and no substantial differences in cell cycle arrest in the nondividing cells were observed. Lifespan extension was correlated with reduced reactive oxygen species during early stationary phase in high Ty1 copy strains, and antioxidant treatment allowed the zero Ty1 copy strain to live as long as high Ty1 copy-number strains in rich medium with hydroxyurea. This exceptional yeast system has identified an unexpected longevity-promoting role for retrotransposons that may yield novel insights into mechanisms regulating lifespan.

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Elevated presence of retrotransposons at sites of DNA double strand break repair in mouse models of metabolic oxidative stress and MYC-induced lymphoma

Cited by 25 publications

References 31 publications

Retrotransposition is associated with genome instability during chronological aging

Retrotransposition is associated with genome instability during chronological aging

Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

Extension of Saccharomyces paradoxus Chronological Lifespan by Retrotransposons in Certain Media Conditions Is Associated with Changes in Reactive Oxygen Species

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