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Dr. Daniele Fachinetti - CENP-A preserves the integrity of centromeric DNA repeats

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Daniele Fachinetti

Institut Curie, Paris

CENP-A preserves the integrity of centromeric DNA repeats

Faithful chromosome segregation is essential to ensure correct transmission of the genetic material and relies on centromeres, complex DNA/protein structures that link chromosomes to the spindle microtubules. In most species, centromeres are composed of repetitive alpha-satellite DNA wrapped around the histone H3 variant CENP-A, the centromere epigenetic mark (Fachinetti et al., 2013). Given their repetitive nature, centromeric DNA sequences may form secondary structures that could potentially induce replication fork stalling and high level of recombination. Interestingly, centromeres are often sites of chromosomal rearrangements in cancers, suggesting an inherent fragility. It was recently demonstrated that CENP-A counteracts aberrant recombination of centromeric repeats (Giunta & Funabiki, 2017), suggesting that a correct chromatin state is required to preserve genome integrity.

By using the auxin-inducible degron system to rapidly remove CENP-A in human cells (Hoffmann et al., 2016), we now show that aberrant recombination and persistent DNA replication occur at dysfunctional centromeres following CENP-A removal in S-phase. These result in accumulation of DNA damage foci, shortening of centromeric DNA and chromosome rearrangements in the following cell cycles. Altogether, our findings point to an essential role of CENP-A in maintaining centromeric repeats stability by preventing the onset of DNA replication stress and chromosome fragility.

Selected references

  • Fachinetti et al. 2017 CENP-A modifications on Ser68 and Lys124 are dispensable for establishment, maintenance, and long-term function of human centromeres. Dev Cell 40(1):104-113
  • Sathyan et al. 2017 α-amino trimethylation of CENP-A by NRMT is required for full recruitment of the centromere. Nat Commun 8:14678
  • Hoffmann et al. 2016 CENP-A is dispensable for mitotic centromere function after initial centromere/kinetochore assembly. Cell Rep 17(9):2394-2404
  • Fachinetti et al. 2015 DNA sequence-specific binding of CENP-B enhances the fidelity of human centromere function. Dev Cell 33(3):314-27
  • Fachinetti et al. 2013 A two-step mechanism for epigenetic specification of centromere identity and function. Nat Cell Biol 15(9):1056-66
  • Holland et al. 2012 Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells. Proc Natl Acad Sci USA 109(49):E3350-7
  • Fachinetti et al. 2010 Replication termination at eukaryotic chromosomes is mediated by Top2 and occurs at genomic loci containing pausing elements. Mol Cell 39(4):595-605

 

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