Alternative titles; symbols
HGNC Approved Gene Symbol: TDP2
SNOMEDCT: 773498006;
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38) : 6:24,649,979-24,666,899 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | Spinocerebellar ataxia, autosomal recessive 23 | 616949 | Autosomal recessive | 3 |
The TDP2 gene encodes a 5-prime tyrosyl-DNA phosphodiesterase that is required for efficient repair of topoisomerase II (TOP2; see 126430)-induced DNA double-strand breaks (Cortes Ledesma et al., 2009).
By performing a yeast 2-hybrid screen on a HeLa cDNA library using a cDNA encoding the cytoplasmic region of CD40 as bait, followed by screening an umbilical vein cDNA library, Pype et al. (2000) isolated a cDNA encoding TTRAP. The deduced 362-amino acid protein contains a potential coiled-coil motif between residues 236 and 250. Northern blot analysis detected a 2.2-kb transcript in all tissues tested, with an additional 1.8-kb transcript in testis. Northern blot and in situ hybridization analysis indicated ubiquitous but variable expression in adult and embryonic mouse tissues, with striking expression in fetal thymus and discrete brain regions.
Gomez-Herreros et al. (2014) found expression of the TDP2 gene in multiple human fetal and adult tissues, with high expression in various brain regions, including the frontal and occipital lobes, the hippocampus, the striatum, and the cerebellum.
By immunoprecipitation and Western blot analysis, Pype et al. (2000) showed that TTRAP interacts with CD40 (109535) and TNFR75 (TNFR2; 191191), as well as with TRAF2 (601895), TRAF3 (601896), TRAF5 (602356), and particularly with the N-terminal half of the TRAF-N domain of TRAF6; TTRAP did not interact with TRADD (603500). The interaction with CD40, but not the interaction with TRAF6, could be enhanced by stimulation of cells with CD40 ligand (CD40LG; 300386). Yeast 2-hybrid and mutation analyses determined that TTRAP binds to amino acids 230 to 245 of CD40, the same region used by TRAF6 but distinct from that used by TRAF2 or TRAF3. Overexpression of TTRAP inhibited nuclear factor kappa-B (NFKB; see 164011) activation without a decreased synthesis of TNFR2 or CD40. Overexpression also did not affect NIK (604655)- or IKKA (600664)-induced NFKB activation or RELA (164014) transactivation in the nucleus.
Members of the tumor necrosis factor (TNF; see 191160) receptor family, which play a role in induction of cell death and regulation of the inflammatory response, transmit their signal through the direct recruitment of TNF receptor-associated factors, or TRAFs (see 602355). CD40 is a member of this family; CD40-mediated signal transduction induces the transcription of a large number of genes implicated in host defense against pathogens (summary by Rodrigues-Lima et al., 2001). By using various bioinformatics-based sequence and structure analyses to identify proteins involved in TNF signaling, Rodrigues-Lima et al. (2001) found that TTRAP is a member of a superfamily of Mg(2+)/Mn(2+)-dependent phosphodiesterases, which includes sphingomyelinases, inositol-phosphatases, and nucleases. TTRAP has significant sequence and structural similarities specifically with APE1 endonuclease (107748), which is involved in both DNA repair and the activation of transcription factors.
Cortes Ledesma et al. (2009) demonstrated that TTRAP cleaves 5-prime-phosphotyrosyl bonds and that this activity efficiently restores 5-prime-phosphate termini at DNA double-strand breaks in preparation for DNA ligation. Cellular depletion of TTRAP results in increased susceptibility and sensitivity to topoisomerase-II-induced DNA double-strand breaks. Cortes Ledesma et al. (2009) concluded that TTRAP is the first human 5-prime-tyrosyl DNA phosphodiesterase to be identified, and they suggested that this enzyme be denoted tyrosyl-DNA phosphodiesterase-2 (TDP2).
In model cell systems, including postmitotic neural cells, Gomez-Herreros et al. (2014) showed that TDP2 is required for normal levels of gene transcription and normal expression of TOP2 (see 126430)-dependent genes.
Schellenberg et al. (2017) found that the SUMO ligase ZNF451 (615708) is a multifunctional DNA repair factor that controls cellular responses to genotoxic DNA-protein crosslinks that play a role in the regulation of DNA topology by TOP2 through the production of transient DNA double-strand breaks. ZNF451 binding to TOP2 cleavage complex (TOP2cc), a protein-DNA crosslink that is the key intermediate in the TOP2 reaction, facilitates a proteasome-independent TDP2 hydrolase activity on stalled TOP2cc. The ZNF451 SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a 'split-SIM' SUMO2 engagement platform. Schellenberg et al. (2017) concluded that these findings uncovered a ZNF451-TDP2-catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.
By genomic sequence analysis, Pype et al. (2000) mapped the TTRAP gene to 6p22.3-p22.1.
In 3 Irish brothers, born of consanguineous parents, with autosomal recessive cerebellar ataxia-23 (SCAR23; 616949), Gomez-Herreros et al. (2014) identified a homozygous splice site mutation in the TDP2 gene (605764.0001). The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cell extracts showed absence of the full-length TDP2 protein and absence of 5-prime TDP activity, consistent with a loss of function. An unrelated Egyptian patient with a similar disorder was homozygous for a truncating mutation in the TDP2 gene (605764.0002).
By whole-exome sequencing in a 6-year-old Caucasian child in the US with SCAR23, Zagnoli-Vieira et al. (2018) identified homozygosity for the same splice site mutation in the TDP2 gene that had been identified by Gomez-Herreros et al. (2014). Western blot analysis did not detect TDP2 protein in patient primary skin fibroblasts. Patient fibroblasts failed to exhibit significant defects in respiratory chain complexes in biochemical assays compared with control human fibroblasts. However, patient fibroblasts showed an inability to rapidly repair topoisomerase-induced DNA double-strand breaks (DSB) in the nucleus and also showed a profound hypersensitivity to this type of DNA damage. Complementation of patient cells with recombinant human TDP2 restored normal rates of nuclear DSB repair.
Gomez-Herreros et al. (2014) found that mice homozygous for a Tpd2 deletion mutation had decreased 5-prime Tdp activity in neural tissues, which was associated with reduced capacity for double-strand break repair in cortical astrocytes and cerebellar granule neurons. Although mutant mice had no detectable neurologic phenotype, histopathologic studies showed a 25 to 30% reduction in the density of interneurons in the molecular layer of the cerebellum, suggesting that Tdp2 is involved in neural development or maintenance.
In 3 Irish brothers, born of consanguineous parents, with autosomal recessive cerebellar ataxia-23 (SCAR23; 616949), Gomez-Herreros et al. (2014) identified a homozygous G-to-A transition in intron 3 of the TDP2 gene (c.425+1G-A, NM_016614.2), resulting in a splice site mutation. Analysis of patient cells showed that the mutant mRNA was both truncated and subject to nonsense-mediated mRNA, consistent with a loss of function. The mutation, which was found by a combination of homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was filtered against the dbSNP (build 134) and Exome Variant Server databases, as well as 128 control individuals and 672 control exomes. Patient cell extracts showed absence of the full-length TDP2 protein and absence of 5-prime TDP activity, although 3-prime TDP activity, conferred by TDP1 (607198), was normal. In addition, patient lymphoblastoid cells were hypersensitive to the TOP2 (126430) poison etoposide. The findings indicated impaired capacity for double-strand break repair.
By whole-exome sequencing in a 6-year-old Caucasian boy in the US with SCAR23, Zagnoli-Vieira et al. (2018) identified homozygosity for the same c.425+1G-A mutation in the TDP2 gene with the same haplotype that had been identified in the patients reported by by Gomez-Herreros et al. (2014). Western blot analysis did not detect TDP2 protein in patient primary skin fibroblasts. Patient fibroblasts failed to exhibit significant defects in respiratory chain complexes in biochemical assays compared with control human fibroblasts. Similar results were found in wildtype A549 cells in comparison the TDP2-mutated A549 cells. However, patient fibroblasts showed an inability to rapidly repair topoisomerase-induced DNA double-strand breaks (DSB) in the nucleus and also showed a profound hypersensitivity to this type of DNA damage. Complementation of patient cells with recombinant human TDP2 restored normal rates of nuclear DSB repair.
In an Egyptian patient with autosomal recessive cerebellar ataxia-23 (SCAR23; 616949), Gomez-Herreros et al. (2014) identified a homozygous c.413_414delinsAA mutation (c.413_414delinsAA, NM_016614.2) in the TDP2 gene, resulting in a frameshift and premature termination (Ser138Ter). The patient reportedly had affected sibs. Activity of TDP2 in patient blood samples was undetectable.
Cortes Ledesma, F. C., El Khamisy, S. F., Zuma, M. C., Osborn, K., Caldecott, K. W. A human 5-prime-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461: 674-678, 2009. [PubMed: 19794497] [Full Text: https://doi.org/10.1038/nature08444]
Gomez-Herreros, F., Schuurs-Hoeijmakers, J. H. M., McCormack, M., Greally, M. T., Rulten, S., Romero-Granados, R., Counihan, T. J., Chaila, E., Conroy, J., Ennis, S., Delanty, N., Cortes-Ledesma, F., de Brouwer, A. P. M., Cavalleri, G. L., El-Khamisy, S. F., de Vries, B. B. A., Caldecott, K. W. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nature Genet. 46: 516-521, 2014. [PubMed: 24658003] [Full Text: https://doi.org/10.1038/ng.2929]
Pype, S., Declercq, W., Ibrahimi, A., Michiels, C., Van Rietschoten, J. G. I., Dewulf, N., de Boer, M., Vandenabeele, P., Huylebroeck, D., Remacle, J. E. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa-B activation. J. Biol. Chem. 275: 18586-18593, 2000. [PubMed: 10764746] [Full Text: https://doi.org/10.1074/jbc.M000531200]
Rodrigues-Lima, F., Josephs, M., Katan, M., Cassinat, B. Sequence analysis identifies TTRAP, a protein that associates with CD40 and TNF receptor-associated factors, as a member of a superfamily of divalent cation-dependent phosphodiesterases. Biochem. Biophys. Res. Commun. 285: 1274-1279, 2001. [PubMed: 11478795] [Full Text: https://doi.org/10.1006/bbrc.2001.5328]
Schellenberg, M. J., Lieberman, J. A., Herrero-Ruiz, A., Butler, L. R., Williams, J. G., Munoz-Cabello, A. M., Mueller, G. A., London, R. E., Cortes-Ledesma, F., Williams, R. S. ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. Science 357: 1412-1416, 2017. [PubMed: 28912134] [Full Text: https://doi.org/10.1126/science.aam6468]
Zagnoli-Vieira, G., Bruni, F., Thompson, K., He, L., Walker, S., de Brouwer, A. P. M., Taylor R. W., Niyazov, D., Caldecott, K. W. Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurol. Genet. 4: e262, 2018. Note: Electronic Article. Erratum: Neurol. Genet. 4: e277, 2018. [PubMed: 30109272] [Full Text: https://doi.org/10.1212/NXG.0000000000000262]