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

TY - JOUR

T1 - Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply

AU - Ask, Katrine

AU - Jasencakova, Zusana

AU - Menard, Patrice

AU - Feng, Yunpeng

AU - Almouzni, Geneviève

AU - Groth, Anja

PY - 2012/4/18

Y1 - 2012/4/18

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Anemia, Dyserythropoietic, Congenital

KW - Cell Cycle Proteins

KW - Chromosomes

KW - DNA Replication

KW - Glycoproteins

KW - HeLa Cells

KW - Histones

KW - Humans

KW - Models, Biological

KW - Molecular Sequence Data

KW - Mutant Proteins

KW - Mutation, Missense

KW - Protein Binding

KW - Protein Interaction Mapping

KW - S Phase

U2 - 10.1038/emboj.2012.55

DO - 10.1038/emboj.2012.55

M3 - Journal article

C2 - 22407294

SN - 0261-4189

VL - 31

SP - 2013

EP - 2023

JO - E M B O Journal

JF - E M B O Journal

IS - 8

ER -