scholarly journals DOCK7 protects against replication stress by promoting RPA stability on chromatin

2021 ◽  
Vol 49 (6) ◽  
pp. 3322-3337
Author(s):  
Ming Gao ◽  
Guijie Guo ◽  
Jinzhou Huang ◽  
Xiaonan Hou ◽  
Hyoungjun Ham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Replication ◽  
Stress Response ◽  
Cancer Cells ◽  
Replication Fork ◽  
Therapeutic Targets ◽  
Critical Factor ◽  
Replication Stress ◽  
Exchange Factor

Abstract RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer.

scholarly journals Physiological and Pathological Roles of RAD52 at DNA Replication Forks

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 402 ◽  
Author(s):  
Eva Malacaria ◽  
Masayoshi Honda ◽  
Annapaola Franchitto ◽  
Maria Spies ◽  
Pietro Pichierri
Keyword(s):  
Dna Replication ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Full Range ◽  
Therapeutic Targets ◽  
Replication Stress ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Rad52 Protein ◽  
New Biomarkers

Understanding basic molecular mechanisms underlying the biology of cancer cells is of outmost importance for identification of novel therapeutic targets and biomarkers for patient stratification and better therapy selection. One of these mechanisms, the response to replication stress, fuels cancer genomic instability. It is also an Achille’s heel of cancer. Thus, identification of pathways used by the cancer cells to respond to replication-stress may assist in the identification of new biomarkers and discovery of new therapeutic targets. Alternative mechanisms that act at perturbed DNA replication forks and involve fork degradation by nucleases emerged as crucial for sensitivity of cancer cells to chemotherapeutics agents inducing replication stress. Despite its important role in homologous recombination and recombinational repair of DNA double strand breaks in lower eukaryotes, RAD52 protein has been considered dispensable in human cells and the full range of its cellular functions remained unclear. Very recently, however, human RAD52 emerged as an important player in multiple aspects of replication fork metabolism under physiological and pathological conditions. In this review, we describe recent advances on RAD52’s key functions at stalled or collapsed DNA replication forks, in particular, the unexpected role of RAD52 as a gatekeeper, which prevents unscheduled processing of DNA. Last, we will discuss how these functions can be exploited using specific inhibitors in targeted therapy or for an informed therapy selection.

scholarly journals MIF is a 3’ flap nuclease that facilitates DNA replication and promotes tumor growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yijie Wang ◽  
Yan Chen ◽  
Chenliang Wang ◽  
Mingming Yang ◽  
Yanan Wang ◽  
...  
Keyword(s):  
Dna Replication ◽  
Tumor Growth ◽  
Dna Synthesis ◽  
Cancer Cells ◽  
Macrophage Migration Inhibitory Factor ◽  
Replication Fork ◽  
Replication Stress ◽  
Nuclease Activity ◽  
Cell Growth Inhibition ◽  
Poor Overall Survival

AbstractHow cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth.

scholarly journals Chromatin as a Platform for Modulating the Replication Stress Response

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 622 ◽  
Author(s):  
Louis-Alexandre Fournier ◽  
Arun Kumar ◽  
Peter Stirling
Keyword(s):  
Dna Replication ◽  
Stress Response ◽  
Replication Fork ◽  
Replication Stress ◽  
Genome Maintenance ◽  
Post Translational Modifications ◽  
Nucleosome Dynamics ◽  
Dna Replication Stress ◽  
Eukaryotic Dna ◽  
Fork Stalling

Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart.

scholarly journals Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells

2018 ◽  
Vol 78 (19) ◽  
pp. 5561-5573 ◽  
Author(s):  
François Bélanger ◽  
Emile Fortier ◽  
Maxime Dubé ◽  
Jean-François Lemay ◽  
Rémi Buisson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Protein A ◽  
Replication Stress ◽  
Replication Protein A ◽  
Replication Protein ◽  
Ovarian Cancer Cells ◽  
Dna Replication Stress

scholarly journals MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress

2021 ◽  
Vol 14 (10) ◽  
pp. 101167
Author(s):  
Jinwen Shi ◽  
Xiaofeng Zhang ◽  
Jin'e Li ◽  
Wenwen Huang ◽  
Yini Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Replication Stress ◽  
Parp Inhibition ◽  
Gastric Cancer Cells ◽  
Dna Replication Stress

scholarly journals RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response

2016 ◽  
Vol 26 (24) ◽  
pp. 3257-3268 ◽  
Author(s):  
Yuan-Cho Lee ◽  
Qing Zhou ◽  
Junjie Chen ◽  
Jingsong Yuan
Keyword(s):  
Dna Replication ◽  
Stress Response ◽  
Binding Protein ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors

Cancer Cell ◽  
2019 ◽  
Vol 35 (3) ◽  
pp. 519-533.e8 ◽  
Author(s):  
Nisha Pillay ◽  
Anthony Tighe ◽  
Louisa Nelson ◽  
Samantha Littler ◽  
Camilla Coulson-Gilmer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Ovarian Cancer Cells

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 Cyclin E expression is associated with high levels of replication stress in triple-negative breast cancer

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Sergi Guerrero Llobet ◽  
Bert van der Vegt ◽  
Evelien Jongeneel ◽  
Rico D. Bense ◽  
Mieke C. Zwager ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Triple Negative ◽  
Cyclin E ◽  
Replication Stress ◽  
Clinical Samples ◽  
Breast Cancers ◽  
Spearman Correlation ◽  
Expression Levels

Abstract Replication stress entails the improper progression of DNA replication. In cancer cells, including breast cancer cells, an important cause of replication stress is oncogene activation. Importantly, tumors with high levels of replication stress may have different clinical behavior, and high levels of replication stress appear to be a vulnerability of cancer cells, which may be therapeutically targeted by novel molecularly targeted agents. Unfortunately, data on replication stress is largely based on experimental models. Further investigation of replication stress in clinical samples is required to optimally implement novel therapeutics. To uncover the relation between oncogene expression, replication stress, and clinical features of breast cancer subgroups, we immunohistochemically analyzed the expression of a panel of oncogenes (Cyclin E, c-Myc, and Cdc25A,) and markers of replication stress (phospho-Ser33-RPA32 and γ-H2AX) in breast tumor tissues prior to treatment (n = 384). Triple-negative breast cancers (TNBCs) exhibited the highest levels of phospho-Ser33-RPA32 (P < 0.001 for all tests) and γ-H2AX (P < 0.05 for all tests). Moreover, expression levels of Cyclin E (P < 0.001 for all tests) and c-Myc (P < 0.001 for all tests) were highest in TNBCs. Expression of Cyclin E positively correlated with phospho-RPA32 (Spearman correlation r = 0.37, P < 0.001) and γ-H2AX (Spearman correlation r = 0.63, P < 0.001). Combined, these data indicate that, among breast cancers, replication stress is predominantly observed in TNBCs, and is associated with expression levels of Cyclin E. These results indicate that Cyclin E overexpression may be used as a biomarker for patient selection in the clinical evaluation of drugs that target the DNA replication stress response.

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