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Codanin‐1, mutated in the anaemic disease CDAI, regulates Asf1 function in S‐phase histone supply

Katrine Ask, Zuzana Jasencakova, Patrice Menard, Yunpeng Feng, Geneviève Almouzni, Anja Groth

Author Affiliations

  1. Katrine Ask1,
  2. Zuzana Jasencakova1,
  3. Patrice Menard1,
  4. Yunpeng Feng1,
  5. Geneviève Almouzni2 and
  6. Anja Groth*,1
  1. 1 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
  2. 2 Institut Curie UMR218‐CNRS, Paris Cedex 05, France
  1. *Corresponding author. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark. Tel.: +45 353 25538; Fax: +45 353 25669; E-mail: anja.groth{at}
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Efficient supply of new histones during DNA replication is critical to restore chromatin organization and maintain genome function. The histone chaperone anti‐silencing function 1 (Asf1) serves a key function in providing H3.1‐H4 to CAF‐1 for replication‐coupled nucleosome assembly. We identify Codanin‐1 as a novel interaction partner of Asf1 regulating S‐phase histone supply. Mutations in Codanin‐1 can cause congenital dyserythropoietic anaemia type I (CDAI), characterized by chromatin abnormalities in bone marrow erythroblasts. Codanin‐1 is part of a cytosolic Asf1–H3.1‐H4–Importin‐4 complex and binds directly to Asf1 via a conserved B‐domain, implying a mutually exclusive interaction with the chaperones CAF‐1 and HIRA. Codanin‐1 depletion accelerates the rate of DNA replication and increases the level of chromatin‐bound Asf1, suggesting that Codanin‐1 guards a limiting step in chromatin replication. Consistently, ectopic Codanin‐1 expression arrests S‐phase progression by sequestering Asf1 in the cytoplasm, blocking histone delivery. We propose that Codanin‐1 acts as a negative regulator of Asf1 function in chromatin assembly. This function is compromised by two CDAI mutations that impair complex formation with Asf1, providing insight into the molecular basis for CDAI disease.

  • Received September 26, 2011.
  • Accepted February 14, 2012.
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