Repetitive Fragile Sites: Centromere Satellite DNA as a Source of Genome Instability in Human Diseases

Black, Elizabeth M.; Giunta, Simona

doi:10.3390/genes9120615

Cited by 85 publications

(77 citation statements)

References 156 publications

(218 reference statements)

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“…As essential regions of the genome have been proposed to behave like fragile sites [80], shedding a new light on CFSs' involvement in promoting genomic instability and in determining the genesis of different types of human disorders is urgently needed.…”

Section: Discussionmentioning

confidence: 99%

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Maccaroni

Balzano

Mirimao

et al. 2020

Genes

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Common fragile sites (CFSs) are particularly vulnerable regions of the genome that become visible as breaks, gaps, or constrictions on metaphase chromosomes when cells are under replicative stress. Impairment in DNA replication, late replication timing, enrichment of A/T nucleotides that tend to form secondary structures, the paucity of active or inducible replication origins, the generation of R-loops, and the collision between replication and transcription machineries on particularly long genes are some of the reported characteristics of CFSs that may contribute to their tissue-specific fragility. Here, we validated the induction of two CFSs previously found in the human fetal lung fibroblast line, Medical Research Council cell strain 5 (MRC-5), in another cell line derived from the same fetal tissue, Institute for Medical Research-90 cells (IMR-90). After induction of CFSs through aphidicolin, we confirmed the expression of the CFS 1p31.1 on chromosome 1 and CFS 3q13.3 on chromosome 3 in both fetal lines. Interestingly, these sites were found to not be fragile in lymphocytes, suggesting a role for epigenetic or transcriptional programs for this tissue specificity. Both these sites contained late-replicating genes NEGR1 (neuronal growth regulator 1) at 1p31.1 and LSAMP (limbic system-associated membrane protein) at 3q13.3, which are much longer, 0.880 and 1.4 Mb, respectively, than the average gene length. Given the established connection between long genes and CFS, we compiled information from the literature on all previously identified CFSs expressed in fibroblasts and lymphocytes in response to aphidicolin, including the size of the genes contained in each fragile region. Our comprehensive analysis confirmed that the genes found within CFSs are longer than the average human gene; interestingly, the two longest genes in the human genome are found within CFSs: Contactin Associated Protein 2 gene (CNTNAP2) in a lymphocytes’ CFS, and Duchenne muscular dystrophy gene (DMD) in a CFS expressed in both lymphocytes and fibroblasts. This indicates that the presence of very long genes is a unifying feature of all CFSs. We also obtained replication profiles of the 1p31.1 and 3q13.3 sites under both perturbed and unperturbed conditions using a combination of fluorescent in situ hybridization (FISH) and immunofluorescence against bromodeoxyuridine (BrdU) on interphase nuclei. Our analysis of the replication dynamics of these CFSs showed that, compared to lymphocytes where these regions are non-fragile, fibroblasts display incomplete replication of the fragile alleles, even in the absence of exogenous replication stress. Our data point to the existence of intrinsic features, in addition to the presence of long genes, which affect DNA replication of the CFSs in fibroblasts, thus promoting chromosomal instability in a tissue-specific manner.

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Section: Discussionmentioning

confidence: 99%

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Maccaroni

Balzano

Mirimao

et al. 2020

Genes

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“…Two clear examples are telomeres and centromeres, which are both heterochromatic regions enriched in repetitive sequences. These chromosomal regions are prone to formation of complex DNA secondary structures, such as stem-loops, G4 structures, and DNA catenanes, which can interfere with replication fork progression and contribute to chromosome fragility (Martínez and Blasco, 2015;Bloom and Costanzo, 2017;Higa et al, 2017;Black and Giunta, 2018). Sophisticated protein complexes regulate telomere and centromere stability and function.…”

Section: Genomic Regions Susceptible To Replication Stressmentioning

confidence: 99%

DNA replication stress: oncogenes in the spotlight

Primo

Teixeira

2020

Genet. Mol. Biol.

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Precise replication of genetic material is essential to maintain genome stability. DNA replication is a tightly regulated process that ensues faithful copies of DNA molecules to daughter cells during each cell cycle. Perturbation of DNA replication may compromise the transmission of genetic information, leading to DNA damage, mutations, and chromosomal rearrangements. DNA replication stress, also referred to as DNA replicative stress, is defined as the slowing or stalling of replication fork progression during DNA synthesis as a result of different insults. Oncogene activation, one hallmark of cancer, is able to disturb numerous cellular processes, including DNA replication. In fact, extensive work has indicated that oncogene-induced replication stress is an important source of genomic instability in human carcinogenesis. In this review, we focus on main oncogenes that induce DNA replication stress, such as RAS, MYC, Cyclin E, MDM2, and BCL-2 among others, and the molecular mechanisms by which these oncogenes interfere with normal DNA replication and promote genomic instability.

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“…Recent advancements in long read sequencing technologies, such as Pacific Biosciences (PB) and Oxford Nanopore Technologies (ONT), led to a substantial increase in the contiguity of genome assemblies (Koren et al, 2017;Kolmogorov et al, 2019;Ruan and Li, 2019;Shafin et al, 2019) and opened a possibility to resolve extra-long tandem repeats ( ETRs ), the problem that was viewed as intractable until recently. Assembling ETRs is important since variations in ETR have been linked to cancer and infertility (Barra and Fachinetti, 2018;Black and Giunta, 2018;Ferreira et al, 2015;Giunta and Funabiki, 2017;Miga et al, 2019;Smurova and De Wulf, 2018;Zhu et al, 2018) . ETR sequencing is also important for addressing open problems about centromere evolution (Alkan et al, 2007;Lower et al, 2018;Shepelev et al, 2009, Henikoff et al, 2015 .…”

Section: Introductionmentioning

confidence: 99%

The String Decomposition Problem and its Applications to Centromere Assembly

Dvorkina

Bzikadze²,

Pevzner

2019

Preprint

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Recent attempts to assemble long tandem repeats (such as multi-megabase long centromeres) faced the challenge of accurate translation of long error-prone reads from the nucleotide alphabet into the alphabet of repeat units . Centromeres represent a particularly complex type of nested tandem repeats , where each unit is itself a repeat formed by chromosome-specific monomers (a repeat within repeat). Given a set of monomers forming a specific centromere, translation of a read into monomers is modeled as the String Decomposition Problem, finding a concatenate of monomers with the highest-scoring sequence alignment to a given read. We developed a StringDecomposer algorithm for solving this problem, benchmarked it on the set of reads generated by the Telomere-to-Telomere consortium, and identified a novel (rare) monomer that extends the set of twelve X-chromosome specific monomers identified more than three decades ago. The accurate translation of each read into a monomer alphabet turns centromere assembly into a more tractable problem than the notoriously difficult problem of assembling centromeres in the nucleotide alphabet. Our identification of a novel monomer emphasizes the importance of careful identification of all (even rare) monomers for follow-up centromere assembly efforts.

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Repetitive Fragile Sites: Centromere Satellite DNA as a Source of Genome Instability in Human Diseases

Cited by 85 publications

References 156 publications

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

Impaired Replication Timing Promotes Tissue-Specific Expression of Common Fragile Sites

DNA replication stress: oncogenes in the spotlight

The String Decomposition Problem and its Applications to Centromere Assembly

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