Poster Presentation Epigenetics 2013

A balancing act between the chaperone NASP and lysosomal degradation to fine-tune histone supply and maintain genome integrity (#120)

Adam J L Cook 1 2 3 , Zachary Gurard-Levin 2 , Isabelle Vassias 2 , David Tremethick 3 , Geneviève Almouzni 2
  1. Centenary Institute of Cancer Medicine & Cell Biology, Newtown, NSW, Australia
  2. Chromatin Dynamics Laboratory, UMR218 CNRS, Institut Curie, Paris, France
  3. John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia

Proper genome packaging and thus genome stability requires coordination of both DNA and histone metabolism. While histone gene transcription and RNA processing can respond to scheduled changes in demand, how histone supply adjusts to unexpected changes in demand remains is less clear. We recently revealed a role for the histone chaperone Nuclear Autoantigenic Sperm Protein (NASP) to protect a reservoir of soluble histones H3-H4 in mammalian somatic cells1 . The reservoir can be fine-tuned, increasing or decreasing depending on the level of NASP. Our data suggest that NASP does so by balancing the activity of the heat-shock proteins Hsc70 and Hsp90 to direct H3-H4 for degradation by chaperone-mediated autophagy. The importance of NASP is revealed upon acute unexpected changes in histone demand and perturbation of histone supply chain function. These insights into NASP function and the existence of a tunable reservoir in mammalian cells demonstrate that contingency is integrated into the histone supply chain to respond to unexpected changes in demand. Curiously, NASP isoform expression is misregulated in cancer cells and it is well-established that improper histone supply causes genome instability, a hallmark of cancer, hinting that NASP plays a functional role in cancer. Our latest efforts to address this question and its link to the maintenance of genome stability will be presented. 

  1. Cook, A.J.L., Gurard-Levin, Z.A., Vassias, I., and Almouzni, G. (2011). A specific function for the histone chaperone NASP to fine-tune a reservoir of soluble H3-H4 in the histone supply chain. Mol. Cell 44, 918–927.