Human TDP1 ELISA Matched Antibody Pair

Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM #607250), an exceedingly rare disorder having been documented in only a single family from Saudi Arabia, is the result of an unusual mutation in the tyrosyl DNA phosphodiesterase 1 gene (TDP1). We performed high-throughput sequencing (whole exome and ataxia gene panel) in two apparently unrelated Omani families segregating sensorimotor neuropathy and ataxia in an autosomal recessive fashion. Following validation by Sanger sequencing, all affected subjects (n = 4) were confirmed to carry the known SCAN1 pathogenic homozygous variant in the TDP1 gene, NM_001008744.1:c.1478A > G (p.His493Arg). In keeping with the initial description, our patients demonstrated progressive ataxia, cerebellar atrophy and disabling axonal sensori-motor neuropathy (n = 4), hypercholesterolemia (n = 2) and elevated serum alpha fetoprotein (n = 3). In addition, our patients also had mild cognitive deficits in multiple domains (n = 3), a feature not previously reported. Our findings independently revalidate the phenotype of TDP1 mutation and expand the clinical spectrum to include mild cognitive deficits. Haplotype sharing, as determined by DNA microarray (CytoScan HD), attests to a possible common founder mutation in the Arab population. (C) 2019 Elsevier Ltd. All rights reserved.

Mutations of DNA repair pathways contribute to tumorigenesis and provide a therapeutic target for synthetic lethal interactions in tumor cells. Given that tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs stalled topoisomerase-I DNA complexes, we hypothesized that inhibition of Tdp1 has synthetic lethal effects in some cancers. To test this, we screened tumor arrays for Tdp1 expression and observed that Tdp1 is expressed in many tumors, including more than 90% of human breast tumors. Subsequent chemical screening identified putative Tdp1 inhibitors. Treatment of control human mammary epithelial cells and the breast cancer cell line MCF-7 with compound CD00509 preferentially sensitized MCF-7 cells to camptothecin and decreased cell proliferation 25% more than camptothecin treatment alone. This suggests that CD00509 specifically targeted Tdp1 in vitro, and CD00509 increased the sensitivity of wild-type murine embryonic fibroblasts (MEFs) to camptothecin to a degree comparable to that of Tdp1(-/-) MEFs. In addition, consistent with poly ADP-ribose polymerase-1 (PARP-1) collaborating with Tdp1 in DNA repair, combined Tdp1 and PARP-1 inhibition was more detrimental to MCF-7 cells than either treatment alone, whereas the combination was not additively harmful to control mammary cells. We conclude that targeting Tdp1 in anticancer therapy preferentially enhances the sensitivity of some breast cancer cells to camptothecin and may be an effective adjuvant for breast cancer therapy.