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 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 Chromatin remodeling factor CHR18 interacts with replication protein RPA1A to regulate the DNA replication stress response in Arabidopsis

2018 ◽  
Vol 220 (2) ◽  
pp. 476-487 ◽  
Author(s):  
Jia-Jia Han ◽  
Ze-Ting Song ◽  
Jing-Liang Sun ◽  
Zheng-Ting Yang ◽  
Meng-Jun Xian ◽  
...  
Keyword(s):  
Dna Replication ◽  
Stress Response ◽  
Chromatin Remodeling ◽  
Replication Stress ◽  
Replication Protein ◽  
Dna Replication Stress

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 LIM Protein Ajuba associates with the RPA complex through direct and cell cycle-dependent interaction with the RPA70 subunit

2017 ◽  
Author(s):  
Sandy Fowler ◽  
Pascal Maguin ◽  
Sampada Kalan ◽  
Diego Loayza
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Genome Stability ◽  
Replication Stress ◽  
Cellular Transformation ◽  
Early Event ◽  
Lim Protein ◽  
Show Evidence ◽  
Dna Replication Stress ◽  
Cycle Dependent

AbstractDNA damage response pathways are essential for genome stability and cell survival. Specifically, the ATR kinase is activated by DNA replication stress. An early event in this activation is the recruitment and phosphorylation of RPA, a single stranded DNA binding complex composed of three subunits, RPA70,RPA32 and RPA14. We have previously shown that the LIM protein Ajuba associates with RPA, and that depletion of Ajuba leads to potent activation of ATR. In this study, we show evidence that the Ajuba-RPA interaction occurs through direct protein contact with RPA70, and that their association is cell cycle-regulated and is reduced upon DNA replication stress. We propose a model in which Ajuba negatively regulates the ATR pathway by directly interacting with RPA70, thereby preventing an inappropriate ATR activation. Our results provide a framework to understand the mechanism of regulation of ATR in human cells, which is important to prevent cellular transformation and tumorigenesis.

scholarly journals FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress

2013 ◽  
Vol 200 (2) ◽  
pp. 141-149 ◽  
Author(s):  
Yeon-Tae Jeong ◽  
Mario Rossi ◽  
Lukas Cermak ◽  
Anita Saraf ◽  
Laurence Florens ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Protein A ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Dna Helicase ◽  
Dna Lesions ◽  
Physical Interaction ◽  
Helicase Activity ◽  
Dna Replication Stress

Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)–binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress, apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress.

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.

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