Retrotransposition is associated with genome instability during chronological aging

Maxwell, Patrick H.; Burhans, William C.; Curcio, M. Joan

doi:10.1073/pnas.1100271108

Cited by 131 publications

(122 citation statements)

References 55 publications

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“…All strains were derivatives of a Ty-less strain of S. paradoxus, DG1768 (MATa,ura3, kindly provided by D. Garfinkel) (Garfinkel et al 2003). A galactose-inducible plasmid copy of Ty1 containing a his3AI retrotransposition indicator gene (Curcio and Garfinkel 1991) was used to obtain derivatives of DG1768 with a single genomic copy of a Ty1his3AI element, as described previously (Maxwell et al 2011). The high copy URA3-marked plasmid pGTy1H3CLA containing an unmarked Ty1 element under the control of a galactose-inducible promoter (Garfinkel et al 1988) was used to introduce unmarked copies of Ty1 into the genome of strain DG1768.…”

Section: Methodsmentioning

confidence: 99%

“…A previously described semiquantitative assay to measure Ty1 integration upstream of 5S rRNA genes was modified in two ways to compare Ty1 retrotransposition levels in different yeast strains (Maxwell et al 2011). First, primers to the S. paradoxus LEU2 gene were used to control for PCR efficiency.…”

Section: Ty1 Integration and Retromobility Frequencymentioning

confidence: 99%

“…Increased expression of retrotransposons with age has been observed in gonads of Caenorhabditis elegans, brains of Drosophila melanogaster, somatic tissues in mice, normal human cells grown ex vivo, and in yeast mother cells (Wang et al 2011;Dennis et al 2012;De Cecco et al 2013a,b;Li et al 2013;Hu et al 2014). Increased mobility of retrotransposons has been detected at late stages of Saccharomyces cerevisiae chronological lifespan (CLS) and in brains of aged D. melanogaster (Maxwell et al 2011;Li et al 2013). Inhibition of elevated Alu retrotransposon expression during senescence of normal human cells grown ex vivo reversed senescence phenotypes (Wang et al 2011).…”

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confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Ty1 Integration and Retromobility Frequencymentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Consistent with the idea that TE activation could contribute toward aging (De Cecco et al ., 2013b; Sedivy et al ., 2013), increased expression of Ty1 retrotransposon is correlated with increased chromosome rearrangements and genome instability in old yeasts (Maxwell et al ., 2011; VanHoute & Maxwell, 2014; Patterson et al ., 2015). …”

Section: Introductionmentioning

confidence: 99%

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

et al. 2016

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SummaryEukaryotic genomes contain transposable elements (TE) that can move into new locations upon activation. Since uncontrolled transposition of TEs, including the retrotransposons and DNA transposons, can lead to DNA breaks and genomic instability, multiple mechanisms, including heterochromatin‐mediated repression, have evolved to repress TE activation. Studies in model organisms have shown that TEs become activated upon aging as a result of age‐associated deregulation of heterochromatin. Considering that different organisms or cell types may undergo distinct heterochromatin changes upon aging, it is important to identify pathways that lead to TE activation in specific tissues and cell types. Through deep sequencing of isolated RNAs, we report an increased expression of many retrotransposons in the old Drosophila fat body, an organ equivalent to the mammalian liver and adipose tissue. This de‐repression correlates with an increased number of DNA damage foci and decreased level of Drosophila lamin‐B in the old fat body cells. Depletion of the Drosophila lamin‐B in the young or larval fat body results in a reduction of heterochromatin and a corresponding increase in retrotransposon expression and DNA damage. Further manipulations of lamin‐B and retrotransposon expression suggest a role of the nuclear lamina in maintaining the genome integrity of the Drosophila fat body by repressing retrotransposons.

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“…Overexpressing TE RNAs is sufficient to cause cytotoxicity, and inhibiting expression of these TEs causes reversal of both senescence and cytotoxic phenotypes (10,11). TE activation has been observed with age in mice (8,12), as well as C. elegans (13), yeast (14), Drosophila (15,16), and senescent human tissue culture cells (7).…”

mentioning

confidence: 99%

Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

Wood

Jones

Jiang

et al. 2016

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

190

201

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Transposable elements (TEs) are mobile genetic elements, highly enriched in heterochromatin, that constitute a large percentage of the DNA content of eukaryotic genomes. Aging in Drosophila melanogaster is characterized by loss of repressive heterochromatin structure and loss of silencing of reporter genes in constitutive heterochromatin regions. Using next-generation sequencing, we found that transcripts of many genes native to heterochromatic regions and TEs increased with age in fly heads and fat bodies. A dietary restriction regimen, known to extend life span, repressed the age-related increased expression of genes located in heterochromatin, as well as TEs. We also observed a corresponding age-associated increase in TE transposition in fly fat body cells that was delayed by dietary restriction. Furthermore, we found that manipulating genes known to affect heterochromatin structure, including overexpression of Sir2, Su(var)3-9, and Dicer-2, as well as decreased expression of Adar, mitigated age-related increases in expression of TEs. Increasing expression of either Su(var)3-9 or Dicer-2 also led to an increase in life span. Mutation of Dicer-2 led to an increase in DNA double-strand breaks. Treatment with the reverse transcriptase inhibitor 3TC resulted in decreased TE transposition as well as increased life span in TE-sensitized Dicer-2 mutants. Together, these data support the retrotransposon theory of aging, which hypothesizes that epigenetically silenced TEs become deleteriously activated as cellular defense and surveillance mechanisms break down with age. Furthermore, interventions that maintain repressive heterochromatin and preserve TE silencing may prove key to preventing damage caused by TE activation and extending healthy life span.aging | heterochromatin | transposable elements | dietary restriction | silencing

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Retrotransposition is associated with genome instability during chronological aging

Cited by 131 publications

References 55 publications

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

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

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

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