DNA Copy Number Variations as Markers of Mutagenic Impact

Hovhannisyan, Galina; Harutyunyan, Tigran; Aroutiounian, Rouben; Liehr, Thomas

doi:10.3390/ijms20194723

Cited by 28 publications

(24 citation statements)

References 84 publications

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“…CNV describes the fact that some sections of the genome may be repeated and the number of these repeats may be different between individuals. CNVs involve 50 bp to over 1,000,000 bp fragments of gene regulatory regions ( 16 ). They are associated with gene expression and phenotype by affecting gene copy number ( 17 ).…”

Section: Chromosomal Rearrangementsmentioning

confidence: 99%

TERT—Regulation and Roles in Cancer Formation

et al. 2020

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Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.

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Section: Chromosomal Rearrangementsmentioning

confidence: 99%

TERT—Regulation and Roles in Cancer Formation

et al. 2020

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“…In contrast, facioscapulohumeral muscular dystrophy is caused by the contraction of D4Z4 macrosatellite repeats comprised of a 3.3-kb unit harboring the DUX4 gene ( 8 ). CNV-mediated environmental adaptation has been well documented in budding yeast ( 9 ). When exposed to high concentrations of copper ions, yeast cells amplify the resistance gene CUP1 to rapidly generate adapted progenies.…”

Section: Introductionmentioning

confidence: 99%

Catalytically inactive Cas9 impairs DNA replication fork progression to induce focal genomic instability

Doi

Okada

Yasukawa

et al. 2021

Nucleic Acids Research

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Catalytically inactive Cas9 (dCas9) has become an increasingly popular tool for targeted gene activation/inactivation, live-cell imaging, and base editing. While dCas9 was reported to induce base substitutions and indels, it has not been associated with structural variations. Here, we show that dCas9 impedes replication fork progression to destabilize tandem repeats in budding yeast. When targeted to the CUP1 array comprising ∼16 repeat units, dCas9 induced its contraction in most cells, especially in the presence of nicotinamide. Replication intermediate analysis demonstrated replication fork stalling in the vicinity of dCas9-bound sites. Genetic analysis indicated that while destabilization is counteracted by the replisome progression complex components Ctf4 and Mrc1 and the accessory helicase Rrm3, it involves single-strand annealing by the recombination proteins Rad52 and Rad59. Although dCas9-mediated replication fork stalling is a potential risk in conventional applications, it may serve as a novel tool for both mechanistic studies and manipulation of genomic instability.

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“…It is estimated that CNVs occur in about 9.5% of the human reference genome [27] . CNVs modulate gene expression by a variety of mechanisms, including simple gene dosage effects, duplication or deletion of the regulatory regions of the target genes, or changes in physical proximity of genes and response elements [28] . It was reported that deletion of EFNB3 gene and CpG hypermethylation of EFNB3 promoter with 63.2% GC content are closely linked to p53 tumor suppressor gene on human chromosome 17p13.1, which might cause the relatively infrequent expression of EFNB3 mRNA in CRC [29] .…”

Section: Discussionmentioning

confidence: 99%

The p53-inducible CLDN7 regulates colorectal tumorigenesis and has prognostic significance

Hou

et al. 2020

Neoplasia

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Most colorectal cancer (CRC) are characterized by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the tumor suppressor p53 gene. Although important, p53 is not the only driver of chromosome 17p loss. In this study, we explored the biological and prognostic significance of genes around p53 on 17p13.1 in CRC. The Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes located between 1000 kb upstream and downstream of p53 gene. The function of CLDN7 was evaluated by both in vitro and in vivo experiments. Quantitative real-time PCR, western blot, and promoter luciferase activity, immunohistochemistry were used to explore the molecular drivers responsible for the development and progression of CRC. The results showed that CLDN7, located between 1000 kb upstream and downstream of p53 gene, were remarkably differentially expressed in tumor and normal tissues. CLDN7 expression also positively associated with p53 level in different stages of the adenoma-carcinoma sequence. Both in vitro and in vivo assays showed that CLDN7 inhibited cell proliferation in p53 wild type CRC cells, but had no effects on p53 mutant CRC cells. Mechanistically, p53 could bind to CLDN7 promoter region and regulate its expression. Clinically, high CLDN7 expression was negatively correlated with tumor size, invasion depth, lymphatic metastasis and AJCC III/IV stage, but was positively associated with favorable prognosis of CRC patients. Collectively, our work uncovers the tumor suppressive function for CLDN7 in a p53-dependent manner, which may mediate colorectal tumorigenesis induced by p53 deletion or mutation.

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DNA Copy Number Variations as Markers of Mutagenic Impact

Cited by 28 publications

References 84 publications

TERT—Regulation and Roles in Cancer Formation

TERT—Regulation and Roles in Cancer Formation

Catalytically inactive Cas9 impairs DNA replication fork progression to induce focal genomic instability

The p53-inducible CLDN7 regulates colorectal tumorigenesis and has prognostic significance

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