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

VanHoute, David Richard; Maxwell, Patrick H.

doi:10.1534/genetics.114.168799

Cited by 17 publications

(19 citation statements)

References 65 publications

(112 reference statements)

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“…In contrast, the many retrotransposition-competent Ty1 elements inhabiting Saccharomyces genomes encode their own inhibitor and, therefore, must balance mutations altering p22 potency with those affecting GAG fitness. Since Ty1 GAG or p22 coding regions have not been detected as an exapted gene capable of inhibiting Ty1 movement, the graduated retrotransposition rate provided by CNC may benefit Saccharomyces and Ty1, as suggested by recent work relating increases in Ty1 copy number with longer chronological life span (95). The Ty1-p22 interaction appears to directly block assembly of functional VLPs in a dosedependent manner and to our knowledge represents a novel and effective way to allow some but not rampant retroelement movement.…”

Section: Discussionmentioning

confidence: 80%

A trans -Dominant Form of Gag Restricts Ty1 Retrotransposition and Mediates Copy Number Control

Saha

Mitchell

Nishida

et al. 2015

J Virol

232

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Saccharomyces cerevisiae and Saccharomyces paradoxus lack the conserved RNA interference pathway and utilize a novel form of copy number control (CNC) to inhibit Ty1 retrotransposition. Although noncoding transcripts have been implicated in CNC, here we present evidence that a truncated form of the Gag capsid protein (p22) or its processed form (p18) is necessary and sufficient for CNC and likely encoded by Ty1 internal transcripts. Coexpression of p22/p18 and Ty1 decreases mobility more than 30,000-fold. p22/p18 cofractionates with Ty1 virus-like particles (VLPs) and affects VLP yield, protein composition, and morphology. Although p22/p18 and Gag colocalize in the cytoplasm, p22/p18 disrupts sites used for VLP assembly. Glutathione Stransferase (GST) affinity pulldowns also suggest that p18 and Gag interact. Therefore, this intrinsic Gag-like restriction factor confers CNC by interfering with VLP assembly and function and expands the strategies used to limit retroelement propagation. IMPORTANCERetrotransposons dominate the chromosomal landscape in many eukaryotes, can cause mutations by insertion or genome rearrangement, and are evolutionarily related to retroviruses such as HIV. Thus, understanding factors that limit transposition and retroviral replication is fundamentally important. The present work describes a retrotransposon-encoded restriction protein derived from the capsid gene of the yeast Ty1 element that disrupts virus-like particle assembly in a dose-dependent manner. This form of copy number control acts as a molecular rheostat, allowing high levels of retrotransposition when few Ty1 elements are present and inhibiting transposition as copy number increases. Thus, yeast and Ty1 have coevolved a form of copy number control that is beneficial to both "host and parasite." To our knowledge, this is the first Gag-like retrotransposon restriction factor described in the literature and expands the ways in which restriction proteins modulate retroelement replication.

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Section: Discussionmentioning

confidence: 80%

A trans -Dominant Form of Gag Restricts Ty1 Retrotransposition and Mediates Copy Number Control

Saha

Mitchell

Nishida

et al. 2015

J Virol

232

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“…Another recent study analyzed Ty1 retrotransposon expression and mobility during chronological aging in S. paradoxus (VanHoute & Maxwell, 2014). Increased expression and mobility of retrotransposons with age have been found in nearly every aging model and thought to promote genome instability during aging (Moskalev et al ., 2013).…”

Section: Resultsmentioning

confidence: 99%

“…However, this study showed that, while the strain expressing Ty1 element had 40-fold increased mobility to the rDNA region, neither Ty1 mobility nor increased mutation rate of a representative Ty1 gene led to chronological lifespan decrease. Furthermore, increased expression of a Ty1 could extend chronological lifespan under certain conditions (VanHoute & Maxwell, 2014). …”

Section: Resultsmentioning

confidence: 99%

Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae

2015

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The concept that mutations cause aging phenotypes could not be directly tested previously due to inability to identify age-related mutations in somatic cells and determine their impact on organismal aging. Here, we subjected Saccharomyces cerevisiae to multiple rounds of replicative aging and assessed de novo mutations in daughters of mothers of different age. Mutations did increase with age, but their low numbers, < 1 per lifespan, excluded their causal role in aging. Structural genome changes also had no role. A mutant lacking thiol peroxidases had the mutation rate well above that of wild-type cells, but this did not correspond to the aging pattern, as old wild-type cells with few or no mutations were dying, whereas young mutant cells with many more mutations continued dividing. In addition, wild-type cells lost mitochondrial DNA during aging, whereas shorter-lived mutant cells preserved it, excluding a causal role of mitochondrial mutations in aging. Thus, DNA mutations do not cause aging in yeast. These findings may apply to other damage types, suggesting a causal role of cumulative damage, as opposed to individual damage types, in organismal aging.

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“…HIV-1 CA’s sensitivity to mutation or genetic fragility is comparable to what we see with Ty1 Gag, as our CNC R analysis supports the idea that Ty1 Gag is under strict structural constraint (Tucker, et al 2015). Lastly, since Ty1 GAG or p22 sequences have not yet been detected as a domesticated gene, the graduated rate provided by CNC may benefit Saccharomyces and Ty1, such as extending chronological life span (VanHoute and Maxwell 2014). …”

Section: A New Paradigm For Inhibiting Gag Functionmentioning

confidence: 99%

A self-encoded capsid derivative restricts Ty1 retrotransposition in Saccharomyces

Garfinkel¹,

Tucker²,

Saha³

et al. 2015

Curr Genet

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Retrotransposons and retroviral insertions have molded the genomes of many eukaryotes. Since retroelements transpose via an RNA intermediate, the additive nature of the replication cycle can result in massive increases in copy number if left unchecked. Host organisms have countered with several defense systems, including domestication of retroelement genes that now act as restriction factors to minimize propagation. We discovered a novel truncated form of the Saccharomyces Ty1 retrotransposon capsid protein, dubbed p22 that inhibits virus-like particle (VLP) assembly and function. The p22 restriction factor expands the repertoire of defense proteins targeting the capsid and highlights a novel host-parasite strategy. Instead of inhibiting all transposition by domesticating the restriction gene as a distinct locus, Ty1 and budding yeast may have coevolved a relationship that allows high levels of transposition when Ty1 copy numbers are low and progressively less transposition as copy numbers rise. Here, we offer a perspective on p22 restriction, including its mode of expression, effect on VLP functions, interactions with its target, properties as a nucleic acid chaperone, similarities to other restriction factors, and future directions.

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

Cited by 17 publications

References 65 publications

A trans -Dominant Form of Gag Restricts Ty1 Retrotransposition and Mediates Copy Number Control

A trans -Dominant Form of Gag Restricts Ty1 Retrotransposition and Mediates Copy Number Control

Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae

A self-encoded capsid derivative restricts Ty1 retrotransposition in Saccharomyces

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