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

Abstract

The authors have noticed that the sequence provided in Materials and methods for siRNA#1 targeting CDAN1 is incorrect, the correct sequence is 5 0 -GGAAAGAAUUCGUACCGUU-3 0 (sense strand). The conclusions drawn from the paper remain unchanged.The authors apologize for any inconvenience caused.

Evidence for the nuclear import of histones H3.1 and H4 as monomers

“…As the soluble extract is a mix of both cytosolic and nuclear components, it is likely that the importin-b proteins, which are predominantly cytosolic under steady-state conditions, represent a re-association with complexes post-lysis, either directly to histone tails or via nuclear localisation sequences within the histones chaperones. Interestingly, we did not identify any accessory factors strongly associated with sNASP or HAT1, but identified numerous factors unique to ASF1b, including the histone chaperones HIRA, CHAF1B and tNASP, components of the MCM helicase, the kinases TLK1 and 2, CDAN1 and TONSL, all of which have been previously identified (Sillje & Nigg, 2001;Mello et al, 2002;Tagami et al, 2004;Groth et al, 2007;Duro et al, 2010;Ask et al, 2012;Klimovskaia et al, 2014). In addition, we found a novel, undocumented interactor, C15orf41, mutations of which have been implicated in congenital dyserythropoietic anaemia (Babbs et al, 2013), similar to CDAN1.…”

“…Biochemical isolation of H3.1 (the replication-dependent H3 variant) containing complexes suggests it folds with H4 soon after synthesis, interacting with a number of histone chaperones to form a cytosolic chaperoning network that coordinates nuclear import (Mosammaparast et al, 2002;Campos et al, 2010;Alvarez et al, 2011;Ask et al, 2012). Key cytosolic events in the proposed pathway include H3.1 and H4 forming a heterodimer in the cytosol and interacting with NASP, ASF1, HAT1 and RbAp46 (Mosammaparast et al, 2002;Campos et al, 2010;Alvarez et al, 2011), HAT1 modification of H4 K5 and K12 by acetylation (Alvarez et al, 2011;Parthun, 2011), modification of H3 K9 by methylation (Pinheiro et al, 2012;Rivera et al, 2015) and association with the importin-b protein IPO4 (Imp4b) (Mosammaparast et al, 2002;Blackwell et al, 2007;Campos et al, 2010;Ask et al, 2012;Keck & Pemberton, 2012;Gurard-Levin et al, 2014;Hammond et al, 2017). In addition, a number of importin-b proteins have been suggested to provide chaperoning roles for basic nuclear cargo including ribosomal proteins and linker histones (Jakel et al, 2002), but not, as yet, the core histones.…”

Modelling erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I)

“…42 How this occurs in the case of CDA-I is not yet clear although previous findings from non-erythroid cell lines show Codanin-1 to be cell cycle regulated 7 and cause an increase in cell cycle rate if over-expressed. 5 The final stages of erythropoiesis involve chromatin and nuclear condensation prior to expulsion of the pyknotic nuclei by enucleation 36,43 and this process is highly organized 44 with chromatin condensation playing an important role. 45 The abnormal spongy heterochromatin observed in CDA-I could have a significant impact on the usual processes that precede enucleation, such as the selective loss of histones.…”

“…2 In ~90% of cases, bi-allelic mutations in one of two genes, CDAN1 (encoding Codanin-1) or C15orf41 are causative, 3,4 with the genetic causes of the remaining ~10% of patients yet to be determined. The observation that Codanin-1 and C15orf41 both directly interact with the histone chaperone ASF1 5,6 implies that the two genes participate in the same pathway. Studies in non-erythroid cells have provided insight into protein function, identifying cell-cycle regulation of CDAN1 3,7 and a potential role in histone supply to the nucleus.…”

“…Studies in non-erythroid cells have provided insight into protein function, identifying cell-cycle regulation of CDAN1 3,7 and a potential role in histone supply to the nucleus. 5 However CDA-I is predominantly an erythroid-restricted disease, and use of erythroblasts for functional analysis would be the most informative way to study CDA-I aetiology and may shed light on how loss-of-function and a range of missense mutations in either gene produces a common erythroid phenotype. Furthermore, as novel C15orf41 or CDAN1 variants are identified, pathogenicity cannot be determined without additional diagnostic evidence specific to CDA-I.…”