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DNA polymerase stalling at structured DNA predicts the stability of short tandem repeats

ABSTRACT: DNA polymerase stalling at structured DNA predicts the stability of short tandem repeats

PROVIDER: PRJNA603735 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10984300_1.fastq.gz	Fastqsanger.gz
	SRR10984300_2.fastq.gz	Fastqsanger.gz
	SRR10984301_1.fastq.gz	Fastqsanger.gz
	SRR10984301_2.fastq.gz	Fastqsanger.gz
	SRR10984302_1.fastq.gz	Fastqsanger.gz

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DNA polymerase stalling at structured DNA predicts the stability of short tandem repeats

Project description:Short tandem repeats (STRs) significantly contribute to de novo mutagenesis, driving phenotypic diversity and genetic disease. Although highly diverse, their low complexity and repetitive nature induces DNA polymerase slippage and stalling, leading to length variation and base substitutions. However, the characterisation of DNA synthesis through STR loci has been restricted to a handful of selected sequences, limiting our broader understanding of their evolutionary behaviour. In order to understand the interplay between the ability of a given STR to impair DNA synthesis and its genomic stability, we developed a high-throughput polymerase extension assay that allows monitoring the kinetics of DNA synthesis at all STR permutations in different lengths in parallel. We have used the assay to map at single-nucleotide resolution the movement of a prototypical A-family replicative DNA polymerase (T7 DNA polymerase) through the repeats over time. From this data we can infer the secondary structure adopted by a given STR from the precise manner in which it stalls polymerase and link this to slippage and point mutation during DNA synthesis.

2020-07-27 | GSE144458 | GEO

DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats.

Project description:BackgroundShort tandem repeats (STRs) contribute significantly to de novo mutagenesis, driving phenotypic diversity and genetic disease. Although highly diverse, their repetitive sequences induce DNA polymerase slippage and stalling, leading to length and sequence variation. However, current studies of DNA synthesis through STRs are restricted to a handful of selected sequences, limiting our broader understanding of their evolutionary behaviour and hampering the characterisation of the determinants of their abundance and stability in eukaryotic genomes.ResultsWe perform a comprehensive analysis of DNA synthesis at all STR permutations and interrogate the impact of STR sequence and secondary structure on their genomic representation and mutability. To do this, we developed a high-throughput primer extension assay that allows monitoring of the kinetics and fidelity of DNA synthesis through 20,000 sequences comprising all STR permutations in different lengths. By combining these measurements with population-scale genomic data, we show that the response of a model replicative DNA polymerase to variously structured DNA is sufficient to predict the complex genomic behaviour of STRs, including abundance and mutational constraints. We demonstrate that DNA polymerase stalling at DNA structures induces error-prone DNA synthesis, which constrains STR expansion.ConclusionsOur data support a model in which STR length in eukaryotic genomes results from a balance between expansion due to polymerase slippage at repeated DNA sequences and point mutations caused by error-prone DNA synthesis at DNA structures.

| S-EPMC7441554 | biostudies-literature

Short tandem repeats are important contributors to silencer elements in T cells

Project description:Short tandem repeats are important contributors to silencer elements in T cells

2023-02-28 | GSE219157 | GEO

Cooptation of tandem DNA repeats for the control of epithelial-to-mesenchymal transition.

Project description:Cooptation of tandem DNA repeats for the control of epithelial-to-mesenchymal transition.

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Switch tandem repeats influence the choice of the alternative end-joining pathway in class switch recombination

Project description:Switch tandem repeats influence the choice of the alternative end-joining pathway in class switch recombination

2022-05-11 | GSE174296 | GEO

Cooptation of tandem DNA repeats for the control of epithelial-to-mesenchymal transition [RNA-Seq]

Project description:During normal or pathological epithelial-to-mesenchymal transition, epithelium-specific gene expression is shut down, with the DNA-binding factor ZEB1 acting as a master suppressor of epithelial identity. Here, we show that ZEB1 occupies primate-specific tandem repeats (TRs) harboring dozens of copies of its DNA-binding motif and located within genomic loci relevant for epithelial identity. Deletion of one such repeat in a quasi-mesenchymal human cancer cell line induced the reacquisition of epithelial features and phenocopied the effects of ZEB1 gene deletion. Since ZEB1 binds clustered motifs in a non-cooperative manner, changes in its nuclear concentration enable graded adjustments of TR occupancy, thus fine-tuning repression level. In addition, high motif density in TRs allows ZEB1 binding (and shutdown of epithelial programs) despite differences in chromatin organization and accessibility among epithelial cell types.

2018-05-02 | GSE88735 | GEO

Cooptation of tandem DNA repeats for the control of epithelial-to-mesenchymal transition [ChIP-Seq]

2018-05-02 | GSE88734 | GEO

Cooptation of tandem DNA repeats for the control of epithelial-to-mesenchymal transition [miRNA-Seq]

2018-05-02 | GSE88733 | GEO

Proteomic analysis of DNA synthesis on a structured DNA template in human cellular extracts: Interplay between NHEJ and replication-associated proteins

Project description:It has been established that short inverted repeats (SIRs) trigger base substitution mutagenesis in human cells. However, how the replication machinery deals with this structured DNA is unknown. We have previously reported that in human cell-free extracts, DNA primer extension using a structured single-stranded DNA template is transiently blocked at DNA hairpins [1](Schmutz et al., 2007). Here, we report the proteomic analysis of proteins bound to the DNA template providing evidence that proteins of the NHEJ pathway, particularly the DNA-PK complex (composed of DNA-PKcs and the Ku70/Ku80 dimer) recognize structured single-stranded DNA. DNA-PKcs inhibition results in the mobilization on the template DNA of the DNA-PK complex, along with other proteins acting downstream in the NHEJ pathway, especially the XRCC4-DNA Ligase 4 complex and the recently identified cofactor PAXX. The retention of NHEJ factors to the template DNA in the absence of DNA-PKcs activity correlates with additional halts of primer extension, suggesting that NHEJ proteins may hinder the progression of the DNA synthesis at these sites. Conversely, hijacking of the DNA-PK complex by double-stranded oligos (dsO) results in a large removal of the pausing sites and an elevated DNA extension efficiency. Overall these results raise the possibility that, upon binding to DNA hairpins formed onto ssDNA during fork progression, the DNA-PK complex may play some role in replication fork dynamics in vivo, role that is however not related to repair of double-strand breaks.

2020-02-04 | PXD011156 | Pride

Short Tandem Repeats - Targeted-Sequencing of human cells for Lineage tracing

Project description:Short Tandem Repeats - Targeted-Sequencing of human cells for Lineage tracing

| PRJEB25050 | ENA