Publications by authors named "Stephen Frenk"

8 Publications

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Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility.

Nat Commun 2021 03 3;12(1):1420. Epub 2021 Mar 3.

Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.

In several species, Piwi/piRNA genome silencing defects cause immediate sterility that correlates with transposon expression and transposon-induced genomic instability. In C. elegans, mutations in the Piwi-related gene (prg-1) and other piRNA deficient mutants cause a transgenerational decline in fertility over a period of several generations. Here we show that the sterility of late generation piRNA mutants correlates poorly with increases in DNA damage signaling. Instead, sterile individuals consistently exhibit altered perinuclear germ granules. We show that disruption of germ granules does not activate transposon expression but induces multiple phenotypes found in sterile prg-1 pathway mutants. Furthermore, loss of the germ granule component pgl-1 enhances prg-1 mutant infertility. Environmental restoration of germ granule function for sterile pgl-1 mutants restores their fertility. We propose that Piwi mutant sterility is a reproductive arrest phenotype that is characterized by perturbed germ granule structure and is phenocopied by germ granule dysfunction, independent of genomic instability.
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http://dx.doi.org/10.1038/s41467-021-21635-0DOI Listing
March 2021

Telomeric small RNAs in the genus .

RNA 2019 09 25;25(9):1061-1077. Epub 2019 Jun 25.

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-3280, USA.

Telomeric DNA is composed of simple tandem repeat sequences and has a G-rich strand that runs 5' to 3' toward the chromosome terminus. Small RNAs with homology to telomeres have been observed in several organisms and could originate from telomeres or from interstitial telomere sequences (ITSs), which are composites of degenerate and perfect telomere repeat sequences found on chromosome arms. We identified small RNAs composed of the telomere sequence (TTAGGC) with up to three mismatches, which might interact with telomeres. We rigorously defined ITSs for genomes of and for two closely related nematodes, and Most telomeric small RNAs with mismatches originated from ITSs, which were depleted from mRNAs but were enriched in introns whose genes often displayed hallmarks of genomic silencing. small RNAs composed of perfect telomere repeats were very rare but their levels increased by several orders of magnitude in and Major small RNA species in begin with a 5' guanine nucleotide, which was strongly depleted from perfect telomeric small RNAs of all three species. Perfect G-rich or C-rich telomeric small RNAs commonly began with 5' UAGGCU and 5' UUAGGC or 5' CUAAGC, respectively. In contrast, telomeric small RNAs with mismatches had a mixture of all four 5' nucleotides. We suggest that perfect telomeric small RNAs have a mechanism of biogenesis that is distinct from known classes of small RNAs and that a dramatic change in their regulation occurred during recent evolution.
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http://dx.doi.org/10.1261/rna.071324.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800518PMC
September 2019

Transgenerational Sterility of Piwi Mutants Represents a Dynamic Form of Adult Reproductive Diapause.

Cell Rep 2018 04;23(1):156-171

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biology, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Environmental stress can induce adult reproductive diapause, a state of developmental arrest that temporarily suspends reproduction. Deficiency for C. elegans Piwi protein PRG-1 results in strains that reproduce for many generations but then become sterile. We found that sterile-generation prg-1/Piwi mutants typically displayed pronounced germ cell atrophy as L4 larvae matured into 1-day-old adults. Atrophied germlines spontaneously reproliferated across the first days of adulthood, and this was accompanied by fertility for day 2-4 adults. Sterile day 5 prg-1 mutant adults remained sterile indefinitely, but providing an alternative food source could restore their fertility. Our data imply that late-generation prg-1 mutants experience a dynamic form of adult reproductive diapause, promoted by stress response, cell death, and RNAi pathways, where delayed fertility and reproductive quiescence represent parallel adaptive developmental outcomes. This may occur in response to a form of "heritable stress" that is transmitted by gametes and epigenetic in nature.
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http://dx.doi.org/10.1016/j.celrep.2018.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918633PMC
April 2018

Gene expression hallmarks of cellular ageing.

Biogerontology 2018 12 28;19(6):547-566. Epub 2018 Feb 28.

Epigenetics Programme, Babraham Institute, Cambridge, UK.

Ageing leads to dramatic changes in the physiology of many different tissues resulting in a spectrum of pathology. Nonetheless, many lines of evidence suggest that ageing is driven by highly conserved cell intrinsic processes, and a set of unifying hallmarks of ageing has been defined. Here, we survey reports of age-linked changes in basal gene expression across eukaryotes from yeast to human and identify six gene expression hallmarks of cellular ageing: downregulation of genes encoding mitochondrial proteins; downregulation of the protein synthesis machinery; dysregulation of immune system genes; reduced growth factor signalling; constitutive responses to stress and DNA damage; dysregulation of gene expression and mRNA processing. These encompass widely reported features of ageing such as increased senescence and inflammation, reduced electron transport chain activity and reduced ribosome synthesis, but also reveal a surprising lack of gene expression responses to known age-linked cellular stresses. We discuss how the existence of conserved transcriptomic hallmarks relates to genome-wide epigenetic differences underlying ageing clocks, and how the changing transcriptome results in proteomic alterations where data is available and to variations in cell physiology characteristic of ageing. Identification of gene expression events that occur during ageing across distant organisms should be informative as to conserved underlying mechanisms of ageing, and provide additional biomarkers to assess the effects of diet and other environmental factors on the rate of ageing.
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http://dx.doi.org/10.1007/s10522-018-9750-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223719PMC
December 2018

Can aging be beneficial?

Aging (Albany NY) 2017 Oct;9(10):2016-2017

Epigenetics Programme, Babraham Institute, Cambridge, UK.

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http://dx.doi.org/10.18632/aging.101313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680549PMC
October 2017

Aging yeast gain a competitive advantage on non-optimal carbon sources.

Aging Cell 2017 06 1;16(3):602-604. Epub 2017 Mar 1.

Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.

Animals, plants and fungi undergo an aging process with remarkable physiological and molecular similarities, suggesting that aging has long been a fact of life for eukaryotes and one to which our unicellular ancestors were subject. Key biochemical pathways that impact longevity evolved prior to multicellularity, and the interactions between these pathways and the aging process therefore emerged in ancient single-celled eukaryotes. Nevertheless, we do not fully understand how aging impacts the fitness of unicellular organisms, and whether such cells gain a benefit from modulating rather than simply suppressing the aging process. We hypothesized that age-related loss of fitness in single-celled eukaryotes may be counterbalanced, partly or wholly, by a transition from a specialist to a generalist life-history strategy that enhances adaptability to other environments. We tested this hypothesis in budding yeast using competition assays and found that while young cells are more successful in glucose, highly aged cells outcompete young cells on other carbon sources such as galactose. This occurs because aged yeast divide faster than young cells in galactose, reversing the normal association between age and fitness. The impact of aging on single-celled organisms is therefore complex and may be regulated in ways that anticipate changing nutrient availability. We propose that pathways connecting nutrient availability with aging arose in unicellular eukaryotes to capitalize on age-linked diversity in growth strategy and that individual cells in higher eukaryotes may similarly diversify during aging to the detriment of the organism as a whole.
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http://dx.doi.org/10.1111/acel.12582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418195PMC
June 2017

The nuclear exosome is active and important during budding yeast meiosis.

PLoS One 2014 11;9(9):e107648. Epub 2014 Sep 11.

Epigenetics Programme, The Babraham Institute, Cambridge, United Kingdom.

Nuclear RNA degradation pathways are highly conserved across eukaryotes and play important roles in RNA quality control. Key substrates for exosomal degradation include aberrant functional RNAs and cryptic unstable transcripts (CUTs). It has recently been reported that the nuclear exosome is inactivated during meiosis in budding yeast through degradation of the subunit Rrp6, leading to the stabilisation of a subset of meiotic unannotated transcripts (MUTs) of unknown function. We have analysed the activity of the nuclear exosome during meiosis by deletion of TRF4, which encodes a key component of the exosome targeting complex TRAMP. We find that TRAMP mutants produce high levels of CUTs during meiosis that are undetectable in wild-type cells, showing that the nuclear exosome remains functional for CUT degradation, and we further report that the meiotic exosome complex contains Rrp6. Indeed Rrp6 over-expression is insufficient to suppress MUT transcripts, showing that the reduced amount of Rrp6 in meiotic cells does not directly cause MUT accumulation. Lack of TRAMP activity stabilises ∼ 1600 CUTs in meiotic cells, which occupy 40% of the binding capacity of the nuclear cap binding complex (CBC). CBC mutants display defects in the formation of meiotic double strand breaks (DSBs), and we see similar defects in TRAMP mutants, suggesting that a key function of the nuclear exosome is to prevent saturation of the CBC complex by CUTs. Together, our results show that the nuclear exosome remains active in meiosis and has an important role in facilitating meiotic recombination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107648PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161446PMC
October 2015