DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation

Abstract

A substantial number of individuals with bone marrow failure (BMF) present with one or more extra-hematopoietic abnormality. This suggests a constitutional or inherited basis, and yet many of them do not fit the diagnostic criteria of the known BMF syndromes. Through exome sequencing, we have now identified a subgroup of these individuals, defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21). They present with global BMF, and one individual developed a hematological cancer (acute myeloid leukemia) in childhood. We show that the encoded protein associates with rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid cells obtained from an affected individual exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced amounts of rRNA. Characterization of mutations revealed impairment in interactions with cofactors (PA2G4, HSPA8, and ZNF622) involved in 60S maturation. DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death. Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.

Mechanistic insight into eukaryotic 60S ribosomal subunit biogenesis by cryo-electron microscopy

“…Remarkably, the recent biochemical analysis of mutants of the human Jjj1 homolog DNAJC21 indicates that the components of this pathway and their functions in recycling of the Ebp1, the homolog of Arx1, are conserved in humans (Tummala et al 2016). The lowresolution reconstruction of a 60S-Arx1-Rei1-Jjj1 complex shows additional density for Jjj1 near the contact site between Rei1 and Arx1 and close to ribosomal protein eL31 in proximity to the tunnel exit ( Fig.…”

“…Nucleolar stress, p53 activation due to failed ribosome biogenesis, bone marrow failure, and a predisposition to cancers are commonly observed in ribosomopathies (Liu and Ellis 2006;Narla and Ebert 2010;Danilova and Gazda 2015). The latest addition to the list of ribosome assembly factors involved in ribosomopathies is DNAJC21, the human homolog of the yeast 60S maturation factor Jjj1, mutations of which have been found to be associated with an inherited bone marrow failure syndrome (Tummala et al 2016).…”

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

“…Approximately 75% to 90% of SDS patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene (7)(8)(9). Since the identification of SBDS in 2003, only 2 other causal SDS genes, DNAJC21 (10,11) and EFL1 (12), have been reported, in contrast to other IBMFSs, for which the situation is the opposite (e.g., >20 loci in Fanconi anemia, >10 loci in Diamond-Blackfan anemia, and several loci in severe congenital neutropenia) (13).…”

New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

“…61,62 DNAJC21 belongs to the highly conserved family of DnaJ (heat shock protein 40) involved in protein translation, folding, unfolding, translocation, and degradation. Like SBDS, DNAJC21 is involved in ribosome biogenesis in the maturation of 60S ribosomal subunit and ubiquitously expressed in human tissues.…”

“…Like SBDS, DNAJC21 is involved in ribosome biogenesis in the maturation of 60S ribosomal subunit and ubiquitously expressed in human tissues. 61,62 The identification of mutations in these 2 genes that are involved in 60S maturation and translational activation of ribosomes suggests a common pathway for SDS. 63 The precise mechanism for the neutropenia (as well as other manifestations) remains elusive, however.…”