DNA replication, transcription, and H3K56 acetylation regulate copy number and stability at tandem repeats

AbstractTandem repeats are inherently unstable and exhibit extensive copy number polymorphisms. Despite mounting evidence for their adaptive potential, the mechanisms associated with regulation of the stability and copy number of tandem repeats remain largely unclear. To study copy number variation at tandem repeats, we used two well-studied repetitive arrays in the budding yeast genome, the ribosomal DNA (rDNA) locus, and the copper-inducible CUP1 gene array. We developed powerful, highly sensitive, and quantitative assays to measure repeat instability and copy number and used them in multiple high-throughput genetic screens to define pathways involved in regulating copy number variation. These screens revealed that rDNA stability and copy number are regulated by DNA replication, transcription, and histone acetylation. Through parallel studies of both arrays, we demonstrate that instability can be induced by DNA replication stress and transcription. Importantly, while changes in stability in response to stress are observed within a few cell divisions, a change in steady state repeat copy number requires selection over time. Further, H3K56 acetylation is required for regulating transcription and transcription-induced instability at the CUP1 array, and restricts transcription-induced amplification. Our work suggests that the modulation of replication and transcription is a direct, reversible strategy to alter stability at tandem repeats in response to environmental stimuli, which provides cells rapid adaptability through copy number variation. Additionally, histone acetylation may function to promote the normal adaptive program in response to transcriptional stress. Given the omnipresence of DNA replication, transcription, and chromatin marks like histone acetylation, the fundamental mechanisms we have uncovered significantly advance our understanding of the plasticity of tandem repeats more generally.

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Long tandem repeats as a form of genomic copy number variation: structure and length polymorphism of a chromosome 5p repeat in control and schizophrenia populations

Psychiatric Genetics ◽

10.1097/ypg.0b013e3283207ff6 ◽

2009 ◽

Vol 19 (2) ◽

pp. 64-71 ◽

Cited By ~ 19

Author(s):

Heather A. Bruce ◽

Nancy Sachs ◽

Dobrila D. Rudnicki ◽

Stephanie G. Lin ◽

Virginia L. Willour ◽

...

Keyword(s):

Copy Number Variation ◽

Length Polymorphism ◽

Copy Number ◽

Tandem Repeats ◽

Genomic Copy Number ◽

Genomic Copy ◽

Number Variation ◽

Chromosome 5P ◽

Genomic Copy Number Variation

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Stimulation of adaptive gene amplification by origin firing under replication fork constraint

10.1101/2021.03.04.433911 ◽

2021 ◽

Author(s):

Alex J Whale ◽

Michelle King ◽

Ryan M Hull ◽

Felix Krueger ◽

Jonathan Houseley

Keyword(s):

Copy Number Variation ◽

Gene Amplification ◽

Copy Number ◽

Replication Fork ◽

Copper Resistance ◽

Template Switching ◽

Adaptive Mutations ◽

Number Variation ◽

H3k56 Acetylation ◽

Break Induced Replication

Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32, factors known to alter the frequency of template switching during break induced replication (BIR). CUP1 amplification is also critically dependent on late firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after firing, leaving an epigenetic scar of H3K56 acetylation that promotes template switching during later break induced replication events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.

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Precise annotation of tick mitochondrial genomes reveals multiple copy number variation of short tandem repeats and one transposon-like element

10.21203/rs.2.19332/v2 ◽

2020 ◽

Author(s):

Ze Chen ◽

Yibo Xuan ◽

Guangcai Liang ◽

Xiaolong Yang ◽

Zhijun Yu ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Short Tandem Repeats ◽

Tandem Repeats ◽

Pcr Amplification ◽

Mitochondrial Genomes ◽

Mt Dna ◽

Dna Variation ◽

Number Variation ◽

Short Tandem

Abstract Background: In the present study, we used long-PCR amplification coupled with Next-Generation Sequencing (NGS) to obtain complete mitochondrial (mt) genomes of individual ticks and unprecedently performed precise annotation of these mt genomes. We aimed to: (1) to develop a simple, cost-effective and accurate method for the study of extremely high AT-content mt genomes within an individual animal containing miniscule DNA (e.g. Dermacentor silvarum); (2) to provide a high-quality reference genome for D. silvarum with precise annotation and also for future studies of other tick mt genomes; and (3) to detect and analyze mt DNA variation within an individual tick.Results: These annotations were confirmed by the PacBio full-length transcriptome data to cover both entire strands of the mitochondrial genomes without any gaps or overlaps. Moreover, two new and important findings were reported for the first time, contributing fundamental knowledge to mt biology. The first was the discovery of a transposon-like element that may eventually reveal much about mechanisms of gene rearrangements in mt genomes. Another finding was that Copy Number Variation (CNV) of Short Tandem Repeats (STRs) account for mitochondrial sequence diversity (heterogeneity) within an individual tick, insect, mouse or human, whereas SNPs were not detected. The CNV of STRs in the protein-coding genes resulted in frameshift mutations in the proteins, which can cause deleterious effects. Mitochondria containing these deleterious STR mutations accumulate in cells and can produce deleterious proteins. Conclusions: We proposed that the accumulation of CNV of STRs in mitochondria may cause aging or diseases. Future tests of the CNV of STRs hypothesis help to ultimately reveal the genetic basis of mitochondrial DNA variation and its consequences (e.g., aging and diseases) in animals. Our study will lead to the reconsideration of the importance of STRs and a unified study of CNV of STRs with longer and shorter repeat units (particularly polynucleotides) in both nuclear and mt genomes.

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The Role of Human Satellite III (1q12) Copy Number Variation in the Adaptive Response during Aging, Stress, and Pathology: A Pendulum Model

Genes ◽

10.3390/genes12101524 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1524

Author(s):

Lev N. Porokhovnik ◽

Natalia N. Veiko ◽

Elizaveta S. Ershova ◽

Svetlana V. Kostyuk

Keyword(s):

Stress Response ◽

Copy Number Variation ◽

Copy Number ◽

Tandem Repeats ◽

Genotoxic Stress ◽

Close Link ◽

Copy Numbers ◽

Number Variation

The pericentric satellite III (SatIII or Sat3) and II tandem repeats recently appeared to be transcribed under stress conditions, and the transcripts were shown to play an essential role in the universal stress response. In this paper, we review the role of human-specific SatIII copy number variation (CNV) in normal stress response, aging and pathology, with a focus on 1q12 loci. We postulate a close link between transcription of SatII/III repeats and their CNV. The accrued body of data suggests a hypothetical universal mechanism, which provides for SatIII copy gain during the stress response, alongside with another, more hypothetical reverse mechanism that might reduce the mean SatIII copy number, likely via the selection of cells with excessively large 1q12 loci. Both mechanisms, working alternatively like swings of the pendulum, may ensure the balance of SatIII copy numbers and optimum stress resistance. This model is verified on the most recent data on SatIII CNV in pathology and therapy, aging, senescence and response to genotoxic stress in vitro.

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Precise annotation of tick mitochondrial genomes reveals multiple copy number variation of short tandem repeats and one transposon-like element

10.21203/rs.2.19332/v1 ◽

2019 ◽

Author(s):

Ze Chen ◽

Xiaofeng Xu ◽

Xiaolong Yang ◽

Zhijun Yu ◽

Stephen C. Barker ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Molecular Phylogenetics ◽

Short Tandem Repeats ◽

Tandem Repeats ◽

Regulation Of Gene Expression ◽

Pcr Amplification ◽

Number Variation ◽

Dna 2 ◽

Short Tandem

Abstract Background: Annotation of mitochondrial (mt) genomes is indispensable for fundamental research in many fields, including mt biochemistry, physiology, and the molecular phylogenetics and evolution of animals. Moreover, high-resolution annotation of animal mt genomes can be used to investigate RNA processing, maturation, degradation, and even the regulation of gene expression. In this study, we used long-PCR amplification combined with Next-Generation Sequencing (NGS) to obtain complete mt genomes of individual ticks and performed precise annotation of these mt genomes. We aimed to: (1) develop a simple, cost-effective and accurate method for the study of extremely high AT-content mt genomes within an individual animal containing miniscule DNA; (2) provide a high-quality reference genome for D. silvarum with precise annotation and also for future studies of other tick mt genomes; and (3) use these mt genomes containing two Control Regions (CRs) to confirm our previous findings from those containing one CR. Results: Based on these mt genome annotations, most of our findings were consistent with those from previous studies. Moreover, two new and important findings were reported for the first time, contributing fundamental knowledge to mt biology. The first was the discovery of a transposon-like element that may eventually reveal much about mechanisms of gene rearrangements in mt genomes. Another finding was that Copy Number Variation (CNV) of Short Tandem Repeats (STRs) account for mitochondrial sequence diversity (heterogeneity) within an individual tick, insect, mouse or human. All the detected DNA variations within a single human cell were CNV of STRs, whereas SNPs were not detected. The CNV of STRs in the protein-coding genes resulted in frameshift mutations in the proteins, which can cause deleterious effects. Mitochondria containing these deleterious STR mutations accumulate in cells and could produce deleterious proteins. Conclusions: We proposed that the accumulation of CNV of STRs in mitochondria causes aging or diseases. Our study will lead to the reconsideration of the importance of STRs and a unified study of CNV of STRs with longer and shorter repeat units (particularly polynucleotides) in both nuclear and mt genomes.

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Genome-wide estimation of firing efficiencies of origins of DNA replication from time-course copy number variation data

BMC Bioinformatics ◽

10.1186/1471-2105-11-247 ◽

2010 ◽

Vol 11 (1) ◽

pp. 247 ◽

Cited By ~ 9

Author(s):

Huaien Luo ◽

Juntao Li ◽

Majid Eshaghi ◽

Jianhua Liu ◽

R Krishna Karuturi

Keyword(s):

Dna Replication ◽

Copy Number Variation ◽

Copy Number ◽

Time Course ◽

Genome Wide ◽

Variation Data ◽

Number Variation ◽

Copy Number Variation Data

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Precise annotation of tick mitochondrial genomes reveals multiple copy number variation of short tandem repeats and one transposon-like element

10.21203/rs.2.19332/v3 ◽

2020 ◽

Author(s):

Ze Chen ◽

Yibo Xuan ◽

Guangcai Liang ◽

Xiaolong Yang ◽

Zhijun Yu ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Short Tandem Repeats ◽

Tandem Repeats ◽

Mitochondrial Genomes ◽

Mt Dna ◽

Dna Variation ◽

Number Variation ◽

Dna 2 ◽

Short Tandem

Abstract Background: In the present study, we used long-PCR amplification coupled with Next-Generation Sequencing (NGS) to obtain complete mitochondrial (mt) genomes of individual ticks and unprecedently performed precise annotation of these mt genomes. We aimed to: (1) to develop a simple, cost-effective and accurate method for the study of extremely high AT-content mt genomes within an individual animal (e.g. Dermacentor silvarum) containing miniscule DNA; (2) to provide a high-quality reference genome for D. silvarum with precise annotation and also for future studies of other tick mt genomes; and (3) to detect and analyze mt DNA variation within an individual tick.Results: These annotations were confirmed by the PacBio full-length transcriptome data to cover both entire strands of the mitochondrial genomes without any gaps or overlaps. Moreover, two new and important findings were reported for the first time, contributing fundamental knowledge to mt biology. The first was the discovery of a transposon-like element that may eventually reveal much about mechanisms of gene rearrangements in mt genomes. Another finding was that Copy Number Variation (CNV) of Short Tandem Repeats (STRs) account for mitochondrial sequence diversity (heterogeneity) within an individual tick, insect, mouse or human, whereas SNPs were not detected. The CNV of STRs in the protein-coding genes resulted in frameshift mutations in the proteins, which can cause deleterious effects. Mitochondria containing these deleterious STR mutations accumulate in cells and can produce deleterious proteins. Conclusions: We proposed that the accumulation of CNV of STRs in mitochondria may cause aging or diseases. Future tests of the CNV of STRs hypothesis help to ultimately reveal the genetic basis of mitochondrial DNA variation and its consequences (e.g., aging and diseases) in animals. Our study will lead to the reconsideration of the importance of STRs and a unified study of CNV of STRs with longer and shorter repeat units (particularly polynucleotides) in both nuclear and mt genomes.

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LINE-1 expression in cancer correlates with DNA damage response, copy number variation, and cell cycle progression

10.1101/2020.06.26.174052 ◽

2020 ◽

Cited By ~ 1

Author(s):

Wilson McKerrow ◽

Xuya Wang ◽

Paolo Mita ◽

Song Cao ◽

Mark Grivainis ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Replication ◽

Copy Number Variation ◽

Dna Damage Response ◽

Copy Number ◽

Host Cells ◽

Cycle Progression ◽

Damage Response ◽

Number Variation

ABSTRACTRetrotransposons are genomic DNA sequences that are capable of copying themselves to new genomic locations via RNA intermediates; LINE-1 is the only retrotransposon that remains autonomous and active in the human genome. The mobility of LINE-1 is largely repressed in somatic tissues, but LINE-1 is active in many cancers. Recent studies using LINE-1 constructs indicate that host cells activate a DNA damage response (DDR) to repair retrotransposition intermediates and resolve conflicts between LINE-1 and DNA replication. Using multi-omic data from the CPTAC project, we found correlations between LINE-1 expression and ATM-MRN-SMC DDR signalling in endometrial cancer and between LINE-1 and the ATR-CHEK1 pathway in p53 wild type breast cancer. This provides evidence that conflicts between LINE-1 and DNA replication occur in at least some human cancers. Furthermore, LINE-1 expression in these cancers is correlated with the total amount of copy number variation genome wide, indicating that, when active in cancer, pointing to a direct impact of LINE-1 associated DNA damage on genome structure. We also find that, in endometrial and ovarian cancer, LINE-1 expression is correlated with the expression of genes that drive cycle progression including E2F3, PLK1 and Aurora kinase B. This study provides evidence, supporting recent work in model cell lines, of a LINE-1/DDR connection in human tumors and raises the possibility of additional interactions between LINE-1 and the cell cycle.

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