Scientific publications

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Scientific publications

2009

• Angela Taddei, Griet Van Houwe, Shigeki Nagai, Ionas Erb,
  Erik van Nimwegen and Susan M. Gasser
  The functional importance of telomere clustering:
  Global changes in gene expression result from SIR
  factor dispersion
  Genome Research, 19:611-625 - Abstract
  Budding yeast telomeres and cryptic mating-type loci are enriched at the nuclear envelope, forming foci that sequester silent information regulators (SIR factors), much as heterochromatic chromocenters in higher eukaryotes sequester HP1. Here we examine the impact of such subcompartments for regulating transcription genome-wide. We show that the efficiency of subtelomeric reporter gene repression depends not only on the strength of SIR factor recruitment by cisacting elements, but also on the accumulation of SIRs in such perinuclear foci. To monitor the effects of disrupting this subnuclear compartment, we performed microarray analyses under conditions that eliminate telomere anchoring, while preserving SIR complex integrity. We found 60 genes reproducibly misregulated. Among those with increased expression, 22% were within 20 kb of a telomere, confirming that the nuclear envelope (NE) association of telomeres helps repress natural subtelomeric genes. In contrast, loci that were down-regulated were distributed over all chromosomes. Half of this ectopic repression was SIR complex dependent. We conclude that released SIR factors can promiscuously repress transcription at nontelomeric genes despite the presence of ‘‘anti-silencing'' mechanisms. Bioinformatic analysis revealed that promoters bearing the PAC (RNA Polymerase A and C promoters) or Abf1 binding consenses are consistently downregulated by mislocalization of SIR factors. Thus, the normal telomeric sequestration of SIRs both favors subtelomeric repression and prevents promiscuous effects at a distinct subset of promoters. This demonstrates that patterns of gene expression can be regulated by changing the spatial distribution of repetitive DNA sequences that bind repressive factors.

2008

• Nagai S., Dubrana K., Rsai-Pflugfelder M., Davidson M.B., Roberts T.M., Brown G.W., Varela E., Hediger F., Gasser S.M. & Krogan N.J.
  Functional targeting of DNA damage to a nuclear pore-associated SUMO-dependent ubiquitin ligase
  Science, 322, 597-602
• Myriam Ruault, Marion Dubarry et Angela Taddei
  Re-positioning genes to the nuclear
  envelope in mammalian cells: impact on transcription
  Trends In Genetics, 24(11): 574-581 - Abstract
  The spatial organization of the genome within the nucleus is thought to contribute to genome functions. A key component of the nuclear architecture is the
  nuclear envelope, which is often associated with inactive chromatin. Studies in budding yeast indicate that nuclear position can directly affect gene function. However, the causal relationship between gene position and gene activity in mammalian cells has been more elusive. Several groups recently addressed this issue by tethering
  genes to the inner nuclear membrane. Their studies show that the nuclear periphery is not refractory to gene transcription, but can modulate the activity of certain genes. The 3D organization of the genome might, thus, provide an additional level of regulation necessary for fine-tuning gene expression.

2007

• Meister P., Taddei A., Ponti A., Baldacci G.#, Gasser S.M.#
  (# These authors contributed equally to this work)
  Spatio-temporal organization of replication is modulated by S-phase checkpoint kinases in fission yeast
  Embo J., 26(5), 1315-1326 - Abstract
  Although the molecular enzymology of DNA replication is well characterized, how and why it occurs in discrete nuclear foci is unclear. Using fission yeast, we show that replication takes place in a limited number of replication foci, whose distribution changes with progression through S phase. These sites define replication factories which contain on average 14 replication forks. We show for the first time that entire foci are mobile, able both to fuse and re-segregate. These foci form distinguishable patterns during S-phase, whose succession is reproducible, defining early-, mid- and late- S phase. In wild-type cells, this same temporal sequence can be detected in the presence of hydroxyurea (HU), despite the reduced rate of replication. However, in cells lacking Cds1, an intra-S checkpoint kinase, replication factories dismantle on HU. Intriguingly, even in the absence of DNA damage the replication foci in cds1 cells assume a novel distribution that is not present in wild-type cells, arguing that Cds1 kinase activity contributes to the spatio-temporal organisation of replication during normal cell growth.