Extrachromosomal rDNA circle

Extrachromosomal rDNA circles (aka ERC) are pieces of extrachromosomal circular DNA (eccDNA) derived from ribosomal DNA (rDNA). Initially found in baker's yeast, these self-replicating circles are suggested to contribute to their aging and found in their aged cells.[1][2][3] Like ordinary eccDNA, they are created by intra-molecular homologous recombination of the chromosome.[4][5][6] The process for intra-molecular homologous recombination is independent of chromosomal replication. The de novo generated circles had exact multiples of tandem copies of 2-kb fragments from cosmid templates. The tandem organization is essential to circle formation. Looping out of organized ribosomal genes in intergenic nontranscribed spacers yielded either large or small repeat circles dependent on large or short repeats of the spacer.[4]

In yeast strains

The Sgs1 gene mutations in yeast mother cells were shown to have accelerated aging, suggesting their function to cellular senescence.[7] ERCs accumulate in old cells and mutations of Sgs1 were found to increase this accumulation, leading to the idea that ERCs lead to shorter lifespan of cells.[8] Vice versa, deletion of Fob1 slows down ERC accumulation and increases lifespan.[9] Accumulated ERCs impair cell proliferation in old cells by interfering with the expression of important cell cycle genes at the G1/S transition and thus delay cell cycle progression.[10] The ERC accumulate in the mother cell during the budding process.[2] Sinclair et al. mentioned a suggested common mechanism between the Sgs1 and WRN genes since they both had age related effects on yeast and human aging respectively.[8][11][12][13]

Borghouts et al., resolved the two mechanisms, retrograde response and the increase in cellular content of ERCs, that affected longevity in yeast. They determined that the generation of ERCs negatively influence the life spans of grande (cells with fully functional mitochondria) and petite (cells with dysfunctional mitochondria) yeast strains.[14]

In Xenopus laevis

Circular extrachromosomal DNA are not only found in yeast but other eukaryotic organisms.[15][16] A regulated formation of eccDNA in preblastua Xenopus embryos has been developed. The population of circular rDNA is decreased in embryos, indicative of the circular rDNA migrating to linear DNA, as was shown in their analysis on 2D gel electrophoresis. The decrease in circular rDNA and the degradation of the amplified rDNA population in early embryo development indicated that the small circular molecules are homologous to the rDNA gene cluster, meaning that an abundance of rDNA sequences are not prone to generating circular chromosomes from random events like breakage of ligation.[15]

In retrograde response

Retrograde response or (regulation) is the general term for mitochondrial signaling and broadly defined as the cellular responses to changes in the functional state of the mitochondria.[17] Poole et al. provided a model that resolves the role of retrograde response in lifespan. They depict a process in which ERC production occurs and shortens lifespan in the TAR1 gene.[18]

See also

References
  1. Sinclair DA, Guarente L (December 1997). "Extrachromosomal rDNA circles--a cause of aging in yeast". Cell. 91 (7): 1033–42. doi:10.1016/S0092-8674(00)80493-6. PMID 9428525.
  2. Nyström T (December 2007). "A bacterial kind of aging". PLOS Genetics. 3 (12): e224. doi:10.1371/journal.pgen.0030224. PMC 2134940. PMID 18085827.
  3. Rédei GP (2008). "ERC (extrachromosomal rDNA circle)". Encyclopedia of Genetics, Genomics, Proteomics and Informatics (3rd ed.). Netherlands: Springer. pp. 629. doi:10.1007/978-1-4020-6754-9_5501. ISBN 978-1-4020-6753-2.
  4. Cohen S, Yacobi K, Segal D (June 2003). "Extrachromosomal circular DNA of tandemly repeated genomic sequences in Drosophila". Genome Research. 13 (6A): 1133–45. doi:10.1101/gr.907603. PMC 403641. PMID 12799349.
  5. "Gene Ontology Term: Extrachromosomal rDNA circle accumulation involved in replicative cell aging". Saccharomyces Genome Database (SGD).
  6. "Gene Ontology Term: Extrachromosomal rDNA circle". Saccharomyces Genome Database (SGD).
  7. Sinclair DA, Mills K, Guarente L (August 1997). "Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants". Science. 277 (5330): 1313–6. doi:10.1126/science.277.5330.1313. PMID 9271578.
  8. Sinclair DA, Mills K, Guarente L (August 1997). "Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants". Science. 277 (5330): 1313–6. doi:10.1126/science.277.5330.1313. PMID 9271578.
  9. Defossez, Pierre-Antoine; Prusty, Reeta; Kaeberlein, Matt; Lin, Su-Ju; Ferrigno, Paul; Silver, Pamela A.; Keil, Ralph L.; Guarente, Leonard (1999-04-01). "Elimination of Replication Block Protein Fob1 Extends the Life Span of Yeast Mother Cells". Molecular Cell. 3 (4): 447–455. doi:10.1016/S1097-2765(00)80472-4. ISSN 1097-2765. PMID 10230397.
  10. Neurohr, G. E.; Terry, R. L.; Sandikci, A.; Zou, K.; Li, H.; Amon, A. (2018). "Deregulation of the G1/S-phase transition is the proximal cause of mortality in old yeast mother cells". Genes & Development. 32 (15–16): 1075–1084. doi:10.1101/gad.312140.118. PMC 6075151. PMID 30042134.
  11. Strehler BL (1986-01-01). "Genetic instability as the primary cause of human aging". Experimental Gerontology. 21 (4–5): 283–319. doi:10.1016/0531-5565(86)90038-0. PMID 3545872. S2CID 34431271.
  12. Adamstone FB, Taylor AB (December 1977). "Nucleolar reorganization in cells of the kidney of the rat and its relation to aging". Journal of Morphology. 154 (3): 459–77. doi:10.1002/jmor.1051540306. PMID 592409. S2CID 23371208.
  13. Weinstein ME, Mukherjee AB (March 1988). "Culture media variation as related to in vitro aging of human fibroblasts: II. Effects on nucleolar number/cell, volume/nucleolus and total nucleolar volume/cell". Mechanisms of Ageing and Development. 42 (3): 215–27. doi:10.1016/0047-6374(88)90048-6. PMID 3367667. S2CID 45691903.
  14. Borghouts C, Benguria A, Wawryn J, Jazwinski SM (February 2004). "Rtg2 protein links metabolism and genome stability in yeast longevity". Genetics. 166 (2): 765–77. doi:10.1534/genetics.166.2.765. PMC 1470750. PMID 15020466.
  15. Cohen S, Menut S, Méchali M (October 1999). "Regulated formation of extrachromosomal circular DNA molecules during development in Xenopus laevis". Molecular and Cellular Biology. 19 (10): 6682–9. doi:10.1128/mcb.19.10.6682. PMC 84653. PMID 10490607.
  16. Gaubatz JW (1990). "Extrachromosomal circular DNAs and genomic sequence plasticity in eukaryotic cells". Mutation Research. 237 (5–6): 271–92. doi:10.1016/0921-8734(90)90009-G. PMID 2079966.
  17. Butow RA, Avadhani NG (April 2004). "Mitochondrial signaling: the retrograde response". Molecular Cell. 14 (1): 1–15. doi:10.1016/s1097-2765(04)00179-0. PMID 15068799.
  18. Poole AM, Kobayashi T, Ganley AR (September 2012). "A positive role for yeast extrachromosomal rDNA circles? Extrachromosomal ribosomal DNA circle accumulation during the retrograde response may suppress mitochondrial cheats in yeast through the action of TAR1". BioEssays. 34 (9): 725–9. doi:10.1002/bies.201200037. PMC 3563013. PMID 22706794.
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