Alternative titles; symbols
HGNC Approved Gene Symbol: DDX11
SNOMEDCT: 702829000;
Cytogenetic location: 12p11.21 Genomic coordinates (GRCh38): 12:31,073,860-31,104,799 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p11.21 | Warsaw breakage syndrome | 613398 | Autosomal recessive | 3 |
Helicases are enzymes that unwind annealed DNA, RNA, or RNA-DNA hybrid duplexes using energy derived from ATP hydrolysis. These enzymes contain 7 highly conserved motifs and participate in various cellular processes, including DNA replication, DNA repair, RNA transcription, and RNA modification. DDX11 belongs to a superfamily of helicases containing an iron-sulfur (Fe-S) motif and a DEAD (asp-glu-ala-asp)/DEAH (asp-glu-ala-his) box. Like other DEAD/DEAH box helicases, DDX11 can unwind both DNA-DNA and DNA-RNA duplexes. DDX11 is involved in the maintenance of genomic stability and cohesion of chromosome arms and centromeres in nucleocytoplasm or in mitotic phase. It is also constitutively localized to nucleoli in interphase cells and functions as a positive regulator of ribosomal RNA (rRNA) biogenesis (summary by Sun et al., 2015).
The yeast Chl1 gene encodes a putative helicase that appears to be essential for normal chromosome transmission. Amann et al. (1996) studied 2 human genes related to the Chl1 gene of Saccharomyces cerevisiae, CHLR1 and CHLR2 (601151). The ORFs of these genes encode proteins with predicted molecular masses of 102 kD. The predicted ORFs of these 2 genes are more than 98% identical, suggesting that they may have redundant functions.
Frank and Werner (1996) used differential display PCR to identify novel cDNAs in keratinocytes whose expression was regulated by keratinocyte growth factor (KGF; 148180). One such clone, termed KRG2 by the authors, was identified, and a full-length cDNA was cloned from a KGF-stimulated keratinocyte cDNA library. Sequence analysis indicated that the KRG2 cDNA encodes an 856-amino acid protein that is 32% identical to yeast CHL1. Southern blot analysis suggested that KRG2 is a member of a multigene family. Northern blot analysis revealed a single 4.3-kb mRNA whose expression is upregulated by KGF.
Sun et al. (2015) reported that DDX1 has a DEAD/DEAH box, an Fe-S domain, 7 conserved helicase domains, a nuclear localization signal, and a glutamic acid-rich region. Immunohistochemical analysis detected endogenous DDX11 colocalized with a nucleolar marker in HeLa and HEK293 cells. Cell fractionation confirmed that DDX11 localized to nucleoli in HeLa cells.
Fan et al. (2002) determined that the DDX11 gene contains 26 exons and spans about 25 kb.
Amann et al. (1996) localized the CHLR1 and CHLR2 genes to chromosomes 12p11 and 12p13 by analysis of somatic cell hybrids and fluorescence in situ hybridization. Fluorescence in situ hybridization indicated that the 2 CHLR gene loci are physically distinct and separated by 8 to 12 Mb. Others had reported the duplication of this region of 12p involving a human expressed sequence tag (EST) and 2 previously uncharacterized cDNAs, which Amann et al. (1996) showed were, in fact, the CHLR genes. Comparison of the CHLR1 and CHLR2 gene sequences with databases showed that a large proportion of these genes, including exons encoding 2 functional domains of the C-terminal region, had been duplicated as part of a large human telomeric repeat sequence found on many human chromosomes. The results suggested that duplication of a relatively large region of chromosome 12p containing this putative helicase gene resulted in the creation of numerous pseudogenes as part of a subtelomeric repeat. Amann et al. (1996) stated that the presence of these helicase pseudogenes, as well as pseudogenes for other genes such as the interleukin-9 receptor (300007), within many subtelomeric regions supported the possibility that the spread of this region is subject to exchange between different chromosomes and may have implications for elucidation of the mechanism of intra- and interchromosomal duplication events.
Amann et al. (1996) found that in vitro transcribed and translated CHLR1 and CHLR2 bound efficiently to single-stranded DNA.
Frank and Werner (1996) used RNase protection assays to determine that serum, EGF, and cytokine IL-1-beta (147720) had no effect on KRG2 expression, while inhibitors of keratinocyte proliferation, such as TGF-beta-1 (190180) and TNF-alpha (191160), caused a slight reduction in KRG2 expression. Frank and Werner (1996) hypothesized that KRG2 may be involved in cell cycle regulation.
Amann et al. (1997) showed that both CHLR1 and CHLR2 are expressed only in proliferating human cell lines. Quiescent normal human fibroblasts stimulated to reenter the cell cycle by addition of serum express CHLR1 and CHLR2 as the cells enter S phase. Furthermore, expression of CHLR1 and CHLR2 is lost when human K562 cells are treated with phorbol ester. Amann et al. (1997) also localized the human CHLR proteins to the nucleolus by indirect immunofluorescence.
Vasa-Nicotera et al. (2005) considered DDX11 as a possible determinant of telomere length in humans. Telomere length is a crucial factor for both normal chromosomal function and senescence. Mean telomere length in humans shows considerable interindividual variation and strong genetic determination. Vasa-Nicotera et al. (2005) performed quantitative trait linkage analysis of mean leukocyte telomere-restriction fragment (TRF) lengths, measured by Southern blotting, in 383 adult subjects comprising 258 sib pairs. Heritability of mean TRF was 81.9% +/- 11.8%. There was significant linkage (lod = 3.20) of mean TRF length to a locus on chromosome 12 (609113) that explained 49% of the overall variability in mean TRF length. Preliminary analyses suggested that DDX11 is a strong candidate gene.
Using a yeast 2-hybrid screen, Parish et al. (2006) showed that the E2 protein of papillomavirus binds to CHLR1. Mutant E2 bound to BRD4 (608749) but failed to bind CHLR1 and correspondingly did not associate with mitotic chromosomes. RNAi-induced depletion of CHLR1 also significantly reduced E2 localization to mitotic chromosomes. Parish et al. (2006) concluded that CHLR1 association is required for loading the papillomavirus E2 protein onto mitotic chromosomes and represents a kinetochore-independent mechanism for viral genome maintenance and segregation.
Using small interfering RNA, Sun et al. (2015) found that knockdown of DDX11 in HeLa or HEK293 cells reduced 47S pre-rRNA content, inhibited reporter activity driven by the rRNA promoter, and reduced cell growth and colony formation. Chromatin immunoprecipitation and coimmunoprecipitation assays showed that DDX11 associated with rDNA and interacted with polymerase I transcriptional machinery, including UBF1 (UBTF; 600673), SL1 (see 604905), and RPA194 (POLR1A; 616404). Serum stimulation of HeLa cells markedly increased expression of DDX11, concomitant with RPA194 and phosphorylated UBF1. DDX11 predominantly bound active, unmethylated rDNA loci in HeLa cells. Knockdown of DDX11 increased heterochromatic structures at rDNA repeats, suppressed UBF activity, and suppressed binding of UBF and RPA194 to rDNA loci.
Using Ddx11-deficient chicken DT40 cells, Abe et al. (2018) showed that Ddx11 played an important role in facilitating DNA repair and averting genomic instability induced by interstrand crosslinks. Ddx11 functioned as a backup for the Fanconi anemia (FA; see 607139) pathway to facilitate repair of bulky lesions by homologous recombination. Ddx11 acted jointly with the Rad9 (603761)-Hus1 (603760)-Rad1 (603153) (9-1-1) checkpoint clamp to repair postreplicative lesions, and its repair action did not affect fork speed or stalled fork stability during DNA replication. Moreover, Ddx11 and Rad17 (603139) acted together and contributed to immunoglobulin variable (IgV) gene diversification by facilitating hypermutation and gene conversion at programmed abasic sites that constituted endogenous replication blocks.
In a patient with Warsaw breakage syndrome (WABS; 613398) who had barely detectable levels of DDX11 protein in his fibroblasts and lymphocytes, van der Lelij et al. (2010) identified compound heterozygosity for 2 mutations in the DDX11 gene: a splice site mutation (601150.0001) on the maternal allele and a 3-bp deletion (601150.0002) on the paternal allele. Introduction of DDX11 cDNA into the lymphoblasts from the affected individual rescued the abnormal phenotype, in terms of both chromosomal morphology and sensitivity to growth inhibition by mitomycin C or camptothecin. Van der Lelij et al. (2010) suggested that, given the hypersensitivity of DDX11-deficient cells for mitomycin C and camptothecin, agents that interfere with DNA replication, DDX11 may function at the interface of replication-coupled DNA repair and sister chromatid cohesion. The mother and the grandmother of the proband, both carriers of the splice site mutation, developed Hodgkin lymphoma and adenocarcinoma of the endometrium, respectively. Van der Lelij et al. (2010) suggested that DDX11 may act as a tumor suppressor gene.
In a consanguineous Lebanese family in which 3 sibs had Warsaw breakage syndrome, Capo-Chichi et al. (2013) identified a homozygous missense mutation in the DDX11 gene (R263Q; 601150.0003) that segregated with disease and was not found in controls. Cultured patient lymphocytes showed increased mitomycin C-induced chromosomal breakage, and biochemical studies of purified recombinant DDX11 demonstrated that the R263Q mutation impaired DDX11 helicase activity by perturbing its DNA binding and DNA-dependent ATP hydrolysis.
By whole-exome sequencing, Alkhunaizi et al. (2018) identified 5 patients with Warsaw breakage syndrome who had novel homozygous or compound heterozygous mutations in the DDX11 gene (see, e.g., R378P, 601150.0004 and V859G, 601150.0005). All of the mutations, which were confirmed by Sanger sequencing, segregated with the phenotype in the families, which were of Italian/Croatian, Pakistani, Saudi, and Egyptian descent. The V859G variant appeared to be a founder mutation.
Sun et al. (2015) stated that deletion of Ddx11 in mice is embryonic lethal. They found that morpholino-mediated knockdown of ddx11 in zebrafish resulted in craniofacial and vertebral defects, including shortened and twisted torsos, longer faces, smaller eyes, low and protuberant mouths, and narrowed eye distance, compared with wildtype. Knockdown of zebrafish ddx11 changed epigenetic modifications at rDNA loci, reduced pol I recruitment to the rDNA promoter, and significantly decreased nascent pre-rRNA levels.
In a 14-year-old boy with Warsaw breakage syndrome (WABS; 613398), van der Lelij et al. (2010) identified compound heterozygosity for 2 mutations in the DDX11 gene: a splice site mutation in intron 22 on the maternal allele (IVS22+2T-C), and a 3-bp deletion (2689_2691del; 601150.0002) in exon 22 on the paternal allele. The splice site mutation led to deletion of the last 10 basepairs of exon 22 from DDX11 cDNA, and the 3-bp deletion resulted in deletion of a highly conserved lysine residue from the DDX11 protein (K897).
For discussion of the splice site mutation (2689_2691del) in intron 22 of the DDX11 gene that was found in compound heterozygous state in a patient with Warsaw breakage syndrome (WABS; 613398) by van der Lelij et al. (2010), see 601150.0001.
By overexpression in HEK293 cells, Sun et al. (2015) found that deletion of K897 reduced DDX11 binding to rDNA promoters and lowered DNA-dependent ATPase activity, consequently reducing rRNA transcription, compared with wildtype DDX11.
In 2 sisters from a consanguineous Lebanese family with Warsaw breakage syndrome (WABS; 613398), Capo-Chichi et al. (2013) identified homozygosity for a 788G-A transition in the DDX11 gene, resulting in an arg263-to-gln (R263Q) substitution at a highly conserved residue in the Fe-S domain. The mutation was present in heterozygosity in the unaffected parents and was not found in 100 Lebanese or 50 Palestinian controls or in 198 control exomes from 30 healthy individuals and 168 patients with other rare diseases. Metaphase cells from lymphocytes of the 2 affected sisters showed an increase in chromosomal breakage after treatment with mitomycin C (86% and 68%, respectively, compared with 10% for the healthy control), and of the patient cells with mitomycin C-induced chromosomal breaks, 46.5% and 44%, respectively, showed centromeric heterochromatin repulsion ('railroads') and premature chromatid separation. Studies with purified recombinant DDX11 showed that the mutant unwound both duplex and 2-stranded antiparallel G-quadruplex DNA much less efficiently than wildtype, with only 3% of forked duplex DNA bound by the mutant in concentrations at which there was near-complete binding by wildtype DDX11. In addition, DNA-dependent ATPase activity of the mutant was 18-fold lower than that of wildtype. Capo-Chichi et al. (2013) concluded that the R263Q mutation negatively affects the ability of DDX11 to bind DNA and to perform DNA-dependent ATP hydrolysis, thus resulting in the mutant's inability to efficiently unwind DNA substrates.
Variant Function
By overexpression in HEK293 cells, Sun et al. (2015) found that the R263Q substitution reduced DDX11 binding to rDNA promoters and lowered DNA-dependent ATPase activity, consequently reducing rRNA transcription, compared with wildtype DDX11.
In a boy (patient 2), born of consanguineous Pakistani parents, with Warsaw breakage syndrome (WABS; 613398), Alkhunaizi et al. (2018) identified homozygosity for a c.1133G-C transversion (c.1133G-C, NM_030653.3) in exon 10 of the DDX11 gene, resulting in an arg378-to-pro (R378P) substitution at a conserved residue in the helicase core domain. The parents were heterozygous for the mutation, which was not present in the ExAC, NHLBI EVS, or gnomAD databases. Functional analysis showed a damaging effect on DDX11 protein stability.
In 2 unrelated patients (patients 3 and 4), born to consanguineous Saudi parents, with Warsaw breakage syndrome (WABS; 613398), Alkhunaizi et al. (2018) identified a c.2576T-G transversion (c.2576T-G, NM_030653.3) in exon 26 of the DDX11 gene, resulting in a val859-to-gly (V859G) substitution at a conserved residue in the helicase motif V domain. The mutation, which was confirmed by Sanger sequencing, segregated with the phenotype in the families. Genotype analysis confirmed that both patients shared the same haplotype, and the variant was found at a carrier frequency of 1 in 1,602 in the Saudi Human Genome Program database, suggesting that V859G is a founder variant in the Saudi population.
Abe, T., Ooka, M., Kawasumi, R., Miyata, K., Takata, M., Hirota, K., Branzei, D. Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites. Proc. Nat. Acad. Sci. 115: 8412-8417, 2018. [PubMed: 30061412] [Full Text: https://doi.org/10.1073/pnas.1803110115]
Alkhunaizi, E., Shaheen, R., Bharti, S. K., Joseph-George, A. M., Chong, K., Abdel-Salam, G. M. H., Alowain, M., Blaser, S. I., Papsin, B. C., Butt, M., Hashem, M., Martin, N., Godoy, R., Brosh, R. M., Jr., Alkuraya, F. S., Chitayat, D. Warsaw breakage syndrome: further clinical and genetic delineation. Am. J. Med. Genet. 176A: 2404-2418, 2018. [PubMed: 30216658] [Full Text: https://doi.org/10.1002/ajmg.a.40482]
Amann, J., Kidd, V. J., Lahti, J. M. Characterization of putative human homologues of the yeast chromosome transmission fidelity gene, CHL1. J. Biol. Chem. 272: 3823-3832, 1997. [PubMed: 9013641] [Full Text: https://doi.org/10.1074/jbc.272.6.3823]
Amann, J., Valentine, M., Kidd, V. J., Lahti, J. M. Localization of Chl1-related helicase genes to human chromosome regions 12p11 and 12p13: similarity between parts of these genes and conserved human telomeric-associated DNA. Genomics 32: 260-265, 1996. [PubMed: 8833153] [Full Text: https://doi.org/10.1006/geno.1996.0113]
Capo-Chichi, J.-M., Bharti, S. K., Sommers, J. A., Yammine, T., Chouery, E., Patry, L., Rouleau, G. A., Samuels, M. E., Hamdan, F. F., Michaud, J. L., Brosh, R. M., Jr., Megarbane, A., Kibar, Z. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Hum. Mutat. 34: 103-107, 2013. [PubMed: 23033317] [Full Text: https://doi.org/10.1002/humu.22226]
Fan, Y., Newman, T., Linardopoulou, E., Trask, B. J. Gene content and function of the ancestral chromosome fusion site in human chromosome 2q13-2q14.1 and paralogous regions. Genome Res. 12: 1663-1672, 2002. [PubMed: 12421752] [Full Text: https://doi.org/10.1101/gr.338402]
Frank, S., Werner, S. The human homologue of the yeast CHL1 gene is a novel keratinocyte growth factor-regulated gene. J. Biol. Chem. 271: 24337-24340, 1996. [PubMed: 8798685] [Full Text: https://doi.org/10.1074/jbc.271.40.24337]
Parish, J. L., Bean, A. M., Park, R. B., Androphy, E. J. ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance. Molec. Cell 24: 867-876, 2006. [PubMed: 17189189] [Full Text: https://doi.org/10.1016/j.molcel.2006.11.005]
Sun, X., Chen, H., Deng, Z., Hu, B., Luo, H., Zeng, X., Han, L., Cai, G., Ma, L. The Warsaw breakage syndrome-related protein DDX11 is required for ribosomal RNA synthesis and embryonic development. Hum. Molec. Genet. 24: 4901-4915, 2015. [PubMed: 26089203] [Full Text: https://doi.org/10.1093/hmg/ddv213]
van der Lelij, P., Chrzanowska, K. H., Godthelp, B. C., Rooimans, M. A., Oostra, A. B., Stumm, M., Zdzienicka, M. Z., Joenje, H., de Winter, J. P. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. Am. J. Hum. Genet. 86: 262-266, 2010. [PubMed: 20137776] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.008]
Vasa-Nicotera, M., Brouilette, S., Mangino, M., Thompson, J. R., Braund, P., Clemitson, J.-R., Mason, A., Bodycote, C. L., Raleigh, S. M., Louis, E., Samani, N. J. Mapping of a major locus that determines telomere length in humans. Am. J. Hum. Genet. 76: 147-151, 2005. Note: Erratum: Am. J. Hum. Genet. 76: 373 only, 2005. [PubMed: 15520935] [Full Text: https://doi.org/10.1086/426734]