scholarly journals Kinetics of DNA Repair in Vicia faba Meristem Regeneration Following Replication Stress

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 88
Author(s):  
Dorota Rybaczek ◽  
Marcelina W. Musiałek ◽  
Jan Vrána ◽  
Beáta Petrovská ◽  
Ewa G. Pikus ◽  
...  
Keyword(s):  
Stress Response ◽  
Vicia Faba ◽  
Ataxia Telangiectasia ◽  
Replication Stress ◽  
Cell Cycle Checkpoint ◽  
Damage Repair ◽  
Cycle Checkpoint ◽  
Stress Response System ◽  
Replication Factors ◽  
Kinetics Of

The astonishing survival abilities of Vicia faba, one the earliest domesticated plants, are associated, among other things, to the highly effective replication stress response system which ensures smooth cell division and proper preservation of genomic information. The most crucial pathway here seems to be the ataxia telangiectasia-mutated kinase (ATM)/ataxia telangiectasia and Rad3-related kinase (ATR)-dependent replication stress response mechanism, also present in humans. In this article, we attempted to take an in-depth look at the dynamics of regeneration from the effects of replication inhibition and cell cycle checkpoint overriding causing premature chromosome condensation (PCC) in terms of DNA damage repair and changes in replication dynamics. We were able to distinguish a unique behavior of replication factors at the very start of the regeneration process in the PCC-induced cells. We extended the experiment and decided to profile the changes in replication on the level of a single replication cluster of heterochromatin (both alone and with regard to its position in the nucleus), including the mathematical profiling of the size, activity and shape. The results obtained during these experiments led us to the conclusion that even “chaotic” events are dealt with in a proper degree of order.

scholarly journals Geminin deletion in mouse oocytes results in impaired embryo development and reduced fertility

2016 ◽  
Vol 27 (5) ◽  
pp. 768-775 ◽  
Author(s):  
Xue-Shan Ma ◽  
Fei Lin ◽  
Zhong-Wei Wang ◽  
Meng-Wen Hu ◽  
Lin Huang ◽  
...  
Keyword(s):  
Embryo Development ◽  
Primordial Follicle ◽  
Early Embryo ◽  
Cell Cycle Checkpoint ◽  
Low Fertility ◽  
Early Embryo Development ◽  
Damage Repair ◽  
Cycle Checkpoint ◽  
Oocyte Meiotic Maturation ◽  
Zygote Stage

Geminin controls proper centrosome duplication, cell division, and differentiation. We investigated the function of geminin in oogenesis, fertilization, and early embryo development by deleting the geminin gene in oocytes from the primordial follicle stage. Oocyte-specific disruption of geminin results in low fertility in mice. Even though there was no evident anomaly of oogenesis, oocyte meiotic maturation, natural ovulation, or fertilization, early embryo development and implantation were impaired. The fertilized eggs derived from mutant mice showed developmental delay, and many were blocked at the late zygote stage. Cdt1 protein was decreased, whereas Chk1 and H2AX phosphorylation was increased, in fertilized eggs after geminin depletion. Our results suggest that disruption of maternal geminin may decrease Cdt1 expression and cause DNA rereplication, which then activates the cell cycle checkpoint and DNA damage repair and thus impairs early embryo development.

scholarly journals ATM’s Role in the Repair of DNA Double-Strand Breaks

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1370
Author(s):  
Atsushi Shibata ◽  
Penny A. Jeggo
Keyword(s):  
Stress Responses ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Checkpoint ◽  
Double Strand Breaks ◽  
Multiple Roles ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Cycle Checkpoint

Ataxia telangiectasia mutated (ATM) is a central kinase that activates an extensive network of responses to cellular stress via a signaling role. ATM is activated by DNA double strand breaks (DSBs) and by oxidative stress, subsequently phosphorylating a plethora of target proteins. In the last several decades, newly developed molecular biological techniques have uncovered multiple roles of ATM in response to DNA damage—e.g., DSB repair, cell cycle checkpoint arrest, apoptosis, and transcription arrest. Combinational dysfunction of these stress responses impairs the accuracy of repair, consequently leading to dramatic sensitivity to ionizing radiation (IR) in ataxia telangiectasia (A-T) cells. In this review, we summarize the roles of ATM that focus on DSB repair.

scholarly journals Oncogenic H-Ras Signaling Differentially Targets Replicative and Specialized DNA Polymerases for Depletion

2020 ◽  
Author(s):  
Wei-chung Tsao ◽  
Raquel Buj ◽  
Katherine M. Aird ◽  
Julia M. Sidorova ◽  
Kristin A. Eckert
Keyword(s):  
Dna Polymerase ◽  
Genome Instability ◽  
Replication Stress ◽  
Cellular Transformation ◽  
Cell Cycle Checkpoint ◽  
Ras Signaling ◽  
Neoplastic Progression ◽  
Cycle Checkpoint ◽  
The Face ◽  
Translational Mechanisms

AbstractOncogene activation significantly alters DNA replication dynamics, causing replication stress and genome instability. However, little is known about DNA polymerase expression and regulation during oncogene-induced replication stress. We discovered that the Pol α catalytic subunit, Pol δ, Pol η and Pol κ are all depleted in response to H-RasG12V overexpression in multiple human cell lines. Distinct transcriptional and post-translational mechanisms mediate replicative and specialized DNA polymerase regulation, respectively, and include both MEK-dependent and -independent pathways. Moreover, Pol η depletion is sufficient to induce a senescence-like growth arrest in non-transformed cells. We provide evidence that H-RasG12V-induced polymerase depletion contributes not only to oncogene-induced replication stress, but also to cell cycle checkpoint enforcement. Polymerase degradation is a protective response, associated with improved cell survival in the face of oncogene-induced stress. Our findings significantly impact our understanding of oncogene-induced cellular transformation and suggest that imbalanced polymerase levels may contribute to neoplastic progression.

scholarly journals Experimental Antioxidant Therapy in Ataxia Telangiectasia

2008 ◽  
Vol 2 ◽  
pp. CMO.S535 ◽  
Author(s):  
Ramune Reliene ◽  
Robert H. Schiestl
Keyword(s):  
Ataxia Telangiectasia ◽  
Genetic Disorder ◽  
Cell Cycle Checkpoint ◽  
Antioxidant Therapy ◽  
Checkpoint Control ◽  
Dna Double Strand Breaks ◽  
Beneficial Effects ◽  
Long Term Study ◽  
Cycle Checkpoint ◽  
Deficient Mice

Ataxia telangiectasia (AT) is a rare genetic disorder characterized by immunodeficiency, early onset neurological degeneration, hypersensitivity to ionizing radiation and a high incidence of lymphoid cancers. The disease results from bi-allelic mutations in the AT mutated ( ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidant therapy may mitigate the symptoms of AT, especially neurological degeneration and tumorigenesis. Consequently, several studies examined the effect of antioxidants in Atm deficient mice used as an animal model of AT. N-acetyl-L-cysteine (NAC), EUK-189, tempol and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested for their chemopreventive properties and had some beneficial effects. In addition to antioxidants, cancer therapeutic agent dexamethasone was examined for cancer prevention in Atm deficient mice. Of the tested antioxidants, only NAC has wide clinical applications due to safety and efficacy and is available as an over-the-counter dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. The short-tem study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced both the incidence and multiplicity of lymphoma.

Integrating stress-response and cell-cycle checkpoint pathways

2001 ◽  
Vol 11 (10) ◽  
pp. 426-433 ◽  
Author(s):  
Amanda K Pearce ◽  
Timothy C Humphrey
Keyword(s):  
Cell Cycle ◽  
Stress Response ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint

scholarly journals Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3415
Author(s):  
Peter H. Goff ◽  
Rashmi Bhakuni ◽  
Thomas Pulliam ◽  
Jung Hyun Lee ◽  
Evan T. Hall ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Ataxia Telangiectasia ◽  
Management Strategies ◽  
Adaptive Immune Response ◽  
Cell Cycle Checkpoint ◽  
Damage Response ◽  
Cycle Checkpoint

Metastatic cancers resistant to immunotherapy require novel management strategies. DNA damage response (DDR) proteins, including ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), have been promising therapeutic targets for decades. Specific, potent DDR inhibitors (DDRi) recently entered clinical trials. Surprisingly, preclinical studies have now indicated that DDRi may stimulate anti-tumor immunity to augment immunotherapy. The mechanisms governing how DDRi could promote anti-tumor immunity are not well understood; however, early evidence suggests that they can potentiate immunogenic cell death to recruit and activate antigen-presenting cells to prime an adaptive immune response. Merkel cell carcinoma (MCC) is well suited to test these concepts. It is inherently immunogenic as ~50% of patients with advanced MCC persistently benefit from immunotherapy, making MCC one of the most responsive solid tumors. As is typical of neuroendocrine cancers, dysfunction of p53 and Rb with upregulation of Myc leads to the very rapid growth of MCC. This suggests high replication stress and susceptibility to DDRi and DNA-damaging agents. Indeed, MCC tumors are particularly radiosensitive. Given its inherent immunogenicity, cell cycle checkpoint deficiencies and sensitivity to DNA damage, MCC may be ideal for testing whether targeting the intersection of the DDR checkpoint and the immune checkpoint could help patients with immunotherapy-refractory cancers.

Oncogenic KIT Induces Replication stress and Confers Cell Cycle Checkpoint Vulnerability in Melanoma

2021 ◽  
Author(s):  
Ching-Ni Njauw ◽  
Zhenyu Ji ◽  
Duc Minh Pham ◽  
Antoine Simoneau ◽  
Raj Kumar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Replication Stress ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint

scholarly journals Biophysical evaluation to categorize pathogenicity of cancer-predisposing mutations identified in the BARD1 BRCT domain

RSC Advances ◽  
2018 ◽  
Vol 8 (59) ◽  
pp. 34056-34068
Author(s):  
Rajan Kumar Choudhary ◽  
M. Quadir Siddiqui ◽  
Nikhil Gadewal ◽  
Nachimuthu Senthil Kumar ◽  
Ekaterina S. Kuligina ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Cell Cycle Checkpoint ◽  
Brct Domain ◽  
Cellular Processes ◽  
Damage Repair ◽  
Cycle Checkpoint

The BRCT domain of BARD1 (BARD1 BRCT) is involved in many cellular processes such as DNA damage repair (DDR) and cell-cycle checkpoint regulation.

scholarly journals Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling

2021 ◽  
Author(s):  
Soumojit Pal ◽  
Benjamin R. Nixon ◽  
Michael S. Glennon ◽  
Puneeth Shridhar ◽  
Sidney L. Satterfield ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stress Response ◽  
Ataxia Telangiectasia ◽  
Ventricular Remodeling ◽  
Gene Mutations ◽  
Replication Stress ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Protein Accumulation ◽  
Myocardial Remodeling

Background Sarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at both the cellular and the organ level, suggesting modifiers regulate the effects of these mutations. We hypothesized that sarcomere dysfunction leads to cardiomyocyte genotoxic stress, and this modifies pathological ventricular remodeling. Methods and Results Using a murine model deficient in the sarcomere protein, Mybpc3 −/− (cardiac myosin‐binding protein 3), we discovered that there was a surge in cardiomyocyte nuclear DNA damage during the earliest stages of cardiomyopathy. This was accompanied by a selective increase in ataxia telangiectasia and rad3‐related phosphorylation and increased p53 protein accumulation. The cause of the DNA damage and DNA damage pathway activation was dysregulated cardiomyocyte DNA synthesis, leading to replication stress. We discovered that selective inhibition of ataxia telangiectasia and rad3 related or cardiomyocyte deletion of p53 reduced pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3 −/− animals. Mice and humans harboring other types of sarcomere gene mutations also had evidence of activation of the replication stress response, and this was associated with cardiomyocyte aneuploidy in all models studied. Conclusions Collectively, our results show that sarcomere mutations lead to activation of the cardiomyocyte replication stress response, which modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.

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