TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks
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ABSTRACT:
PROVIDER: PRJNA939255 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28009824_1.fastq.gz | Fastqsanger.gz | |||
| SRR28009824_2.fastq.gz | Fastqsanger.gz | |||
| SRR28009825_1.fastq.gz | Fastqsanger.gz | |||
| SRR28009825_2.fastq.gz | Fastqsanger.gz | |||
| SRR28009826_1.fastq.gz | Fastqsanger.gz |
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Project description:TDP1 removes transcription-blocking TOP1 cleavage complexes (TOP1ccs) and its inactivating H493R mutation causes the neurodegenerative syndrome SCAN1. However, the molecular mechanism underlying SCAN1 phenotype is unclear. Here, we generate human SCAN1 cell models using CRISPR/Cas9 and show that they accumulate TOP1ccs along with changes in gene expression and genomic distribution of R-loops. SCAN1 cells also accumulate transcriptional DNA double-strand breaks (DSBs) specifically in the G1 cell population due to increased DSB formation and lack of repair, both resulting from abortive removal of transcription-blocking TOP1ccs. Deficient TDP1 activity causes increased DSB production and the presence of mutated TDP1 protein hampers DSB repair by a TDP2-dependent back-up pathway. This study provides powerful models to study TDP1 functions under physiological and pathological conditions and unravels that a gain of function of the mutated TDP1 protein, which prevents DSB repair, rather than a loss of TDP1 activity itself, could contribute to SCAN1 pathogenesis.
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Project description:Tdp1, tyrosyl-DNA phosphodiesterase 1, is an enzyme responsible for the repair of DNA breaks resulting from aberrant topoisomerase 1 activity, called Top1 cleavage complexes (Top1-CCs). Mutation of Tdp1 leads to a progressive neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). We have generated tdp1-/- zebrafish as a model for SCAN1. The adult fish have a behavioral defect and hypersensitivity to camptothecin (CPT), a Top1 poison. Strikingly, the embryos do not show increased sensitivity to CPT, unlike any other reported vertebrate models, suggesting genetic compensation is at play at this stage. We thus carried out microarray analysis in CPT-treated zebrafish embryos to compare the gene expression profiles of tdp1WT and tdp1-/- genotypes. Gene expression analysis revealed 1,8111 genes that were differentially expressed: 1,071 were upregulated and 740 were downregulated. Sprtn and neil1, two potential compensation candidates were upregulated in the tdp1-/- embryos.
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Project description:Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a rare recessive neurodegenerative syndrome associated with cerebellar atrophy and peripheral neuropathy. It is caused by a homozygous missense mutation in the tyrosyl-DNA phosphodiesterase-1 (TDP1) gene (A1478G). resulting in a substitution of histidine for arginine-493 (H493R) in the TDP1 catalytic site, leading to reduced TDP1 activity. How TDP1 H493R mutation promotes the SCAN1 phenotype, which is associated with the death of post-mitotic neurons, is unclear. We have generated models of osteosarcoma U2OS cells homozygous for TDP1 H493R employing the CRISPR-Cas9 technique (2 clones, named “1P” and “3.3”). Here, we have generated transcriptional genome wide profile in order to characterize differences in gene expression that are specific of TDP1-mutated clones.
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Project description:Topoisomerase 1 (Top1) removes supercoils from DNA during replication and transcription, is critical for mitotic progression to the G1 phase, and ensures DNA topology. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1ccs). Here, we identify CDK1-dependent phosphorylation of TDP1 at S61 residue during mitosis. TDP1 defective for S61 phosphorylation (TDP1S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via MUS81-dependent mitotic DNA repair mechanism. Replication stress (RS) induced by Camptothecin (CPT) or Aphidicolin (APH) leads to TDP1S61A enrichment at common fragile sites (CFSs), which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in 53BP1 nuclear bodies in the G1-phase. Our findings provide a new insight into the cell cycle-dependent regulation of TDP1 dynamics forthe repair of trapped Top1ccs during mitosis that prevents genomic instability following RS.
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