scholarly journals The impact of transcription-mediated replication stress on genome instability and human disease

2020 ◽  
Vol 1 (5) ◽  
pp. 207-234
Author(s):  
Stefano Gnan ◽  
Yaqun Liu ◽  
Manuela Spagnuolo ◽  
Chun-Long Chen
Keyword(s):  
Dna Replication ◽  
Gene Transcription ◽  
Human Disease ◽  
Genome Stability ◽  
Genome Instability ◽  
Current Knowledge ◽  
Replication Stress ◽  
Genome Replication ◽  
Living Organisms ◽  
The Impact

Abstract DNA replication is a vital process in all living organisms. At each cell division, > 30,000 replication origins are activated in a coordinated manner to ensure the duplication of > 6 billion base pairs of the human genome. During differentiation and development, this program must adapt to changes in chromatin organization and gene transcription: its deregulation can challenge genome stability, which is a leading cause of many diseases including cancers and neurological disorders. Over the past decade, great progress has been made to better understand the mechanisms of DNA replication regulation and how its deregulation challenges genome integrity and leads to human disease. Growing evidence shows that gene transcription has an essential role in shaping the landscape of genome replication, while it is also a major source of endogenous replication stress inducing genome instability. In this review, we discuss the current knowledge on the various mechanisms by which gene transcription can impact on DNA replication, leading to genome instability and human disease.

scholarly journals ARID1A regulates R-loop associated DNA replication stress

2020 ◽  
Author(s):  
Shuhe Tsai ◽  
Emily Yun-chia Chang ◽  
Louis-Alexandre Fournier ◽  
James P. Wells ◽  
Sean W. Minaker ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Clear Cell ◽  
Replication Stress ◽  
Clear Cell Ovarian Carcinoma ◽  
Dna Replication Stress ◽  
Cancer Types ◽  
The Impact ◽  
Oncogenic Gene ◽  
Transcription And Replication

ABSTRACTARID1A is lost in up to 7% of all cancers, and this frequency increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeller complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

scholarly journals ARID1A regulates R-loop associated DNA replication stress

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009238
Author(s):  
Shuhe Tsai ◽  
Louis-Alexandre Fournier ◽  
Emily Yun-chia Chang ◽  
James P. Wells ◽  
Sean W. Minaker ◽  
...  
Keyword(s):  
Dna Replication ◽  
Chromatin Remodeling ◽  
Genome Stability ◽  
Replication Stress ◽  
Clear Cell Ovarian Carcinoma ◽  
Chromatin Remodeling Complexes ◽  
Dna Replication Stress ◽  
Cancer Types ◽  
The Impact ◽  
Transcription And Replication

ARID1A is a core DNA-binding subunit of the BAF chromatin remodeling complex, and is lost in up to 7% of all cancers. The frequency of ARID1A loss increases in certain cancer types, such as clear cell ovarian carcinoma where ARID1A protein is lost in about 50% of cases. While the impact of ARID1A loss on the function of the BAF chromatin remodeling complexes is likely to drive oncogenic gene expression programs in specific contexts, ARID1A also binds genome stability regulators such as ATR and TOP2. Here we show that ARID1A loss leads to DNA replication stress associated with R-loops and transcription-replication conflicts in human cells. These effects correlate with altered transcription and replication dynamics in ARID1A knockout cells and to reduced TOP2A binding at R-loop sites. Together this work extends mechanisms of replication stress in ARID1A deficient cells with implications for targeting ARID1A deficient cancers.

scholarly journals Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability

2019 ◽  
Vol 218 (12) ◽  
pp. 3943-3953 ◽  
Author(s):  
Divya Achuthankutty ◽  
Roshan Singh Thakur ◽  
Peter Haahr ◽  
Saskia Hoffmann ◽  
Alexandros P. Drainas ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cellular Response ◽  
Genome Stability ◽  
Genome Instability ◽  
Replication Stress ◽  
Regulatory Control ◽  
Replicative Stress ◽  
Dna Replication Stress ◽  
Stress Dependent ◽  
Atr Kinase

The ATR kinase is a master regulator of the cellular response to DNA replication stress. Activation of ATR relies on dual pathways involving the TopBP1 and ETAA1 proteins, both of which harbor ATR-activating domains (AADs). However, the exact contribution of the recently discovered ETAA1 pathway to ATR signaling in different contexts remains poorly understood. Here, using an unbiased CRISPR-Cas9–based genome-scale screen, we show that the ATR-stimulating function of ETAA1 becomes indispensable for cell fitness and chromosome stability when the fidelity of DNA replication is compromised. We demonstrate that the ATR-activating potential of ETAA1 is controlled by cell cycle– and replication stress–dependent phosphorylation of highly conserved residues within its AAD, and that the stimulatory impact of these modifications is required for the ability of ETAA1 to prevent mitotic chromosome abnormalities following replicative stress. Our findings suggest an important role of ETAA1 in protecting against genome instability arising from incompletely duplicated DNA via regulatory control of its ATR-stimulating potential.

scholarly journals Genome replication affects transcription factor binding mediating the cascade of herpes simplex virus transcription

2019 ◽  
Vol 116 (9) ◽  
pp. 3734-3739 ◽  
Author(s):  
Sarah E. Dremel ◽  
Neal A. DeLuca
Keyword(s):  
Transcription Factor ◽  
Herpes Simplex Virus ◽  
Dna Replication ◽  
Herpes Simplex ◽  
Gene Transcription ◽  
Transcription Initiation ◽  
Genome Replication ◽  
Pol Ii ◽  
Factor Binding ◽  
Simplex Virus

In herpes simplex virus type 1 (HSV-1) infection, the coupling of genome replication and transcription regulation has been known for many years; however, the underlying mechanism has not been elucidated. We performed a comprehensive transcriptomic assessment and factor-binding analysis for Pol II, TBP, TAF1, and Sp1 to assess the effect genome replication has on viral transcription initiation and elongation. The onset of genome replication resulted in the binding of TBP, TAF1, and Pol II to previously silent late promoters. The viral transcription factor, ICP4, was continuously needed in addition to DNA replication for activation of late gene transcription initiation. Furthermore, late promoters contain a motif that closely matches the consensus initiator element (Inr), which robustly bound TAF1 postreplication. Continued DNA replication resulted in reduced binding of Sp1, TBP, and Pol II to early promoters. Therefore, the initiation of early gene transcription is attenuated following DNA replication. Herein, we propose a model for how viral DNA replication results in the differential utilization of cellular factors that function in transcription initiation, leading to the delineation of kinetic class in HSV-productive infection.

scholarly journals Protective Mechanisms Against DNA Replication Stress in the Nervous System

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 730
Author(s):  
Clara Forrer Charlier ◽  
Rodrigo A. P. Martins
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Replication ◽  
Neurological Diseases ◽  
Replication Stress ◽  
Nervous System Development ◽  
Stress Generation ◽  
Genome Replication ◽  
Cns Development ◽  
Dna Replication Stress

The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

scholarly journals Multi-BRCT Domain Protein Brc1 Links Rhp18/Rad18 and γH2A To Maintain Genome Stability during S Phase

2017 ◽  
Vol 37 (22) ◽  
Author(s):  
Michael C. Reubens ◽  
Sophie Rozenzhak ◽  
Paul Russell
Keyword(s):  
Genome Stability ◽  
Genome Instability ◽  
Replication Stress ◽  
S Phase ◽  
Dna Lesions ◽  
Brct Domain ◽  
Replication Forks ◽  
Content Type ◽  
Domain Protein ◽  
Chromosome Integrity

ABSTRACT DNA replication involves the inherent risk of genome instability, since replisomes invariably encounter DNA lesions or other structures that stall or collapse replication forks during the S phase. In the fission yeast Schizosaccharomyces pombe, the multi-BRCT domain protein Brc1, which is related to budding yeast Rtt107 and mammalian PTIP, plays an important role in maintaining genome integrity and cell viability when cells experience replication stress. The C-terminal pair of BRCT domains in Brc1 were previously shown to bind phosphohistone H2A (γH2A) formed by Rad3/ATR checkpoint kinase at DNA lesions; however, the putative scaffold interactions involving the N-terminal BRCT domains 1 to 4 of Brc1 have remained obscure. Here, we show that these domains bind Rhp18/Rad18, which is an E3 ubiquitin protein ligase that has crucial functions in postreplication repair. A missense allele in BRCT domain 4 of Brc1 disrupts binding to Rhp18 and causes sensitivity to replication stress. Brc1 binding to Rhp18 and γH2A are required for the Brc1 overexpression suppression of smc6-74, a mutation that impairs the Smc5/6 structural maintenance of chromosomes complex required for chromosome integrity and repair of collapsed replication forks. From these findings, we propose that Brc1 provides scaffolding functions linking γH2A, Rhp18, and Smc5/6 complex at damaged replication forks.

scholarly journals The yeast core spliceosome maintains genome integrity through R-loop prevention and α-tubulin expression

2018 ◽  
Author(s):  
Annie S. Tam ◽  
Veena Mathew ◽  
Tianna S. Sihota ◽  
Anni Zhang ◽  
Peter C. Stirling
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Genome Instability ◽  
Genome Integrity ◽  
Genome Maintenance ◽  
Maintenance Factors ◽  
Spindle Assembly Checkpoint Protein

To achieve genome stability cells must coordinate the action of various DNA transactions including DNA replication, repair, transcription and chromosome segregation. How transcription and RNA processing enable genome stability is only partly understood. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in a panel yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the α-tubulin gene TUB1 restores genome integrity. Thus, while R-loops contribute in some settings, defects in yeast splicing predominantly lead to genome instability through effects on gene expression.

scholarly journals MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

2018 ◽  
Author(s):  
Emily Yun-chia Chang ◽  
James P. Wells ◽  
Shu-Huei Tsai ◽  
Yan Coulombe ◽  
Yujia A. Chan ◽  
...  
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Replication Fork ◽  
Genome Instability ◽  
Human Cancer ◽  
Replication Stress ◽  
Maintenance Factors ◽  
Genome Wide ◽  
A Genome ◽  
Dna Replication Stress

SUMMARYEctopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.

scholarly journals Histone dynamics during DNA replication stress

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Chia-Ling Hsu ◽  
Shin Yen Chong ◽  
Chia-Yeh Lin ◽  
Cheng-Fu Kao
Keyword(s):  
Stress Responses ◽  
Genome Stability ◽  
Genome Instability ◽  
Replication Stress ◽  
Dna Lesions ◽  
Protective Mechanisms ◽  
Replication Process ◽  
Dna Replication Stress ◽  
External Sources

AbstractAccurate and complete replication of the genome is essential not only for genome stability but also for cell viability. However, cells face constant threats to the replication process, such as spontaneous DNA modifications and DNA lesions from endogenous and external sources. Any obstacle that slows down replication forks or perturbs replication dynamics is generally considered to be a form of replication stress, and the past decade has seen numerous advances in our understanding of how cells respond to and resolve such challenges. Furthermore, recent studies have also uncovered links between defects in replication stress responses and genome instability or various diseases, such as cancer. Because replication stress takes place in the context of chromatin, histone dynamics play key roles in modulating fork progression and replication stress responses. Here, we summarize the current understanding of histone dynamics in replication stress, highlighting recent advances in the characterization of fork-protective mechanisms.

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