Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles

Andrés Mansisidor, Temistocles Molinar, Priyanka Srivastava, Demetri D. Dartis, Adriana Pino Delgado, Hannah G. Blitzblau, Hannah Klein, Andreas Hochwagen

Research output: Contribution to journalArticle

Abstract

Copy-number changes generate phenotypic variability in health and disease. Whether organisms protect against copy-number changes is largely unknown. Here, we show that Saccharomyces cerevisiae monitors the copy number of its ribosomal DNA (rDNA) and rapidly responds to copy-number loss with the clonal amplification of extrachromosomal rDNA circles (ERCs) from chromosomal repeats. ERC formation is replicative, separable from repeat loss, and reaches a dynamic steady state that responds to the addition of exogenous rDNA copies. ERC levels are also modulated by RNAPI activity and diet, suggesting that rDNA copy number is calibrated against the cellular demand for rRNA. Last, we show that ERCs reinsert into the genome in a dosage-dependent manner, indicating that they provide a reservoir for ultimately increasing rDNA array length. Our results reveal a DNA-based mechanism for rapidly restoring copy number in response to catastrophic gene loss that shares fundamental features with unscheduled copy-number amplifications in cancer cells.

Original languageEnglish (US)
Pages (from-to)583-593
Number of pages11
JournalMolecular Cell
Volume72
Issue number3
DOIs
StatePublished - Nov 1 2018

Fingerprint

Ribosomal DNA
DNA
Oligonucleotide Array Sequence Analysis
Saccharomyces cerevisiae
Genome
Diet
Health
Genes
Neoplasms

Keywords

  • copy-number variations
  • eccDNA
  • Fob1
  • genome instability
  • Hmo1
  • rDNA
  • rRNA genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Mansisidor, A., Molinar, T., Srivastava, P., Dartis, D. D., Pino Delgado, A., Blitzblau, H. G., ... Hochwagen, A. (2018). Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles. Molecular Cell, 72(3), 583-593. https://doi.org/10.1016/j.molcel.2018.08.036

Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles. / Mansisidor, Andrés; Molinar, Temistocles; Srivastava, Priyanka; Dartis, Demetri D.; Pino Delgado, Adriana; Blitzblau, Hannah G.; Klein, Hannah; Hochwagen, Andreas.

In: Molecular Cell, Vol. 72, No. 3, 01.11.2018, p. 583-593.

Research output: Contribution to journalArticle

Mansisidor, A, Molinar, T, Srivastava, P, Dartis, DD, Pino Delgado, A, Blitzblau, HG, Klein, H & Hochwagen, A 2018, 'Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles', Molecular Cell, vol. 72, no. 3, pp. 583-593. https://doi.org/10.1016/j.molcel.2018.08.036
Mansisidor A, Molinar T, Srivastava P, Dartis DD, Pino Delgado A, Blitzblau HG et al. Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles. Molecular Cell. 2018 Nov 1;72(3):583-593. https://doi.org/10.1016/j.molcel.2018.08.036
Mansisidor, Andrés ; Molinar, Temistocles ; Srivastava, Priyanka ; Dartis, Demetri D. ; Pino Delgado, Adriana ; Blitzblau, Hannah G. ; Klein, Hannah ; Hochwagen, Andreas. / Genomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles. In: Molecular Cell. 2018 ; Vol. 72, No. 3. pp. 583-593.
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