scholarly journals Ataxia–telangiectasia mutated coordinates the ovarian DNA repair and atresia-initiating response to phosphoramide mustard

2019 ◽  
Vol 102 (1) ◽  
pp. 248-260
Author(s):  
Kendra L Clark ◽  
Aileen F Keating
Keyword(s):  
Dna Repair ◽  
Ataxia Telangiectasia ◽  
Gene Mutations ◽  
Cell Cycle Checkpoints ◽  
Surface Epithelium ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Interacting Protein ◽  
Primordial Follicles ◽  
Phosphoramide Mustard

Abstract Ataxia–telangiectasia-mutated (ATM) protein recognizes and repairs DNA double strand breaks through activation of cell cycle checkpoints and DNA repair proteins. Atm gene mutations increase female reproductive cancer risk. Phosphoramide mustard (PM) induces ovarian DNA damage and destroys primordial follicles, and pharmacological ATM inhibition prevents PM-induced follicular depletion. Wild-type (WT) C57BL/6 or Atm+/− mice were dosed once intraperitoneally with sesame oil (95%) or PM (25 mg/kg) in the proestrus phase of the estrous cycle and ovaries harvested 3 days thereafter. Atm+/− mice spent ~25% more time in diestrus phase than WT. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) on ovarian protein was performed and bioinformatically analyzed. Relative to WT, Atm+/− mice had 64 and 243 proteins increased or decreased in abundance, respectively. In WT mice, PM increased 162 and decreased 20 proteins. In Atm+/− mice, 173 and 37 proteins were increased and decreased, respectively, by PM. Exportin-2 (XPO2) was localized to granulosa cells of all follicle stages and was 7.2-fold greater in Atm+/− than WT mice. Cytoplasmic FMR1-interacting protein 1 was 6.8-fold lower in Atm+/− mice and was located in the surface epithelium with apparent translocation to the ovarian medulla post-PM exposure. PM induced γH2AX, but fewer γH2AX-positive foci were identified in Atm+/− ovaries. Similarly, cleaved caspase-3 was lower in the Atm+/− PM-treated, relative to WT mice. These findings support ATM involvement in ovarian DNA repair and suggest that ATM functions to regulate ovarian atresia.

scholarly journals Effect of ATR Inhibition in RT Response of HPV-Negative and HPV-Positive Head and Neck Cancers

2021 ◽  
Vol 22 (4) ◽  
pp. 1504
Author(s):  
Rüveyda Dok ◽  
Mary Glorieux ◽  
Marieke Bamps ◽  
Sandra Nuyts
Keyword(s):  
Head And Neck ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Checkpoints ◽  
Specific Cell ◽  
Ataxia Telangiectasia Mutated ◽  
Checkpoint Kinase 1 ◽  
Hpv Status ◽  
Damage Response ◽  
Xenograft Models ◽  
Potential Use

Radiotherapy (RT) has a central role in head and neck squamous cell carcinoma (HNSCC) treatment. Targeted therapies modulating DNA damage response (DDR) and more specific cell cycle checkpoints can improve the radiotherapeutic response. Here, we assessed the influence of ataxia-telangiectasia mutated and Rad3-related (ATR) inhibition with the ATR inhibitor AZD6738 on RT response in both human papillomavirus (HPV)-negative and HPV-positive HNSCC. We found that ATR inhibition enhanced RT response in HPV-negative and HPV-positive cell lines independent of HPV status. The radiosensitizing effect of AZD6738 was correlated with checkpoint kinase 1 (CHK1)-mediated abrogation of G2/M-arrest. This resulted in the inhibition of RT-induced DNA repair and in an increase in the percentage of micronucleated cells. We validated the enhanced RT response in HPV-negative and HPV-positive xenograft models. These data demonstrate the potential use of ATR inhibition in combination with RT as a treatment option for both HPV-negative and HPV-positive HNSCC patients.

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.

ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 1887-1896 ◽  
Author(s):  
Irina R. Matei ◽  
Rebecca A. Gladdy ◽  
Lauryl M. J. Nutter ◽  
Angelo Canty ◽  
Cynthia J. Guidos ◽  
...  
Keyword(s):  
T Cell ◽  
Ataxia Telangiectasia ◽  
Cell Receptor ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Apoptotic Pathway ◽  
Strand Breaks ◽  
Striking Contrast

Abstract Mutations in ATM (ataxia-telangiectasia mutated) cause ataxia-telangiectasia (AT), a disease characterized by neurodegeneration, sterility, immunodeficiency, and T-cell leukemia. Defective ATM-mediated DNA damage responses underlie many aspects of the AT syndrome, but the basis for the immune deficiency has not been defined. ATM associates with DNA double-strand breaks (DSBs), and some evidence suggests that ATM may regulate V(D)J recombination. However, it remains unclear how ATM loss compromises lymphocyte development in vivo. Here, we show that T-cell receptor β (TCRβ)–dependent proliferation and production of TCRβlow CD4+CD8+ (DP) thymocytes occurred normally in Atm−/− mice. In striking contrast, the postmitotic maturation of TCRβlow DP precursors into TCRβint DP cells and TCRβhi mature thymocytes was profoundly impaired. Furthermore, Atm−/− thymocytes expressed abnormally low amounts of TCRα mRNA and protein. These defects were not attributable to the induction of a BCL-2–sensitive apoptotic pathway. Rather, they were associated with frequent biallelic loss of distal Va gene segments in DP thymocytes, revealing that ATM maintains Tcra locus integrity as it undergoes V(D)J recombination. Collectively, our data demonstrate that ATM loss increases the frequency of aberrant Tcra deletion events, which compromise DP thymocyte maturation and likely promote the generation of oncogenic TCR translocations.

scholarly journals Ataxia-telangiectasia Mutated Kinase (ATM) as a Central Regulator of Radiation-induced DNA Damage Response

2010 ◽  
Vol 53 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Aleš Tichý ◽  
Jiřina Vávrová ◽  
Jaroslav Pejchal ◽  
Martina Řezáčová
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response ◽  
Radiation Induced ◽  
Inducible Protein

Ataxia-telangiectasia mutated kinase (ATM) is a DNA damage-inducible protein kinase, which phosphorylates plethora of substrates participating in DNA damage response. ATM significance for the cell faith is undeniable, since it regulates DNA repair, cell-cycle progress, and apoptosis. Here we describe its main signalling targets and discuss its importance in DNA repair as well as novel findings linked to this key regulatory enzyme in the terms of ionizing radiationinduced DNA damage.

DDRE-25. WSD0628: A BRAIN PENETRABLE ATM INHIBITOR AS A RADIOSENSITIZER FOR THE TREATMENT OF GBM AND METASTATIC CNS TUMOR

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi79-vi79
Author(s):  
wei zhong ◽  
Lily Liu ◽  
Claire Sun ◽  
Zhihua Mu
Keyword(s):  
Dna Repair ◽  
Ataxia Telangiectasia ◽  
Aldehyde Oxidase ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Atm Kinase ◽  
Strand Breaks ◽  
Significant Prolongation ◽  
Orally Bioavailable

Abstract ATM (ataxia telangiectasia mutated) kinase, activated by DNA double-strand breaks, promotes DNA repair as well as activates DNA damage checkpoint and plays a key role for resistance to radiotherapy and chemotherapy. ATM function loss confers hypersensitivity to ionizing radiation evidenced by ataxia-telangiectasia (A-T) cells. Thus, pharmacological inhibition of ATM kinase is expected to suppress DSB DNA repair, block checkpoint controls and enhance the therapeutic effect of radiotherapy and other DNA double-strand breaks-inducing chemotherapy. Herein, we report a discovery of a potent, selective, orally bioavailable, and brain penetrable ATM inhibitor WSD0628, as a radiosensitizer for GBM and metastatic CNS tumors with IC50 against ATM < 1nM with high selectivity ( >400 folds) for ATR and DNA-PK. WSD0628 is highly selective over other kinases. In-vitro MDCKII transfected cells and Caco-2 assays have shown that WSD0628 is highly permeable and not a substrate of P-gp or BCRP, two main efflux transporters expressed on human BBB. Preclinical CNS PK studies in rat and mouse confirmed good brain penetration of WSD0628 with Kp,uu,brain and Kp,uu,csf > 0.3. Significant prolongation of overall survival for mice bearing GBM PDX intracranial model was achieved by treatment with WSD0628 (5mpk, QD) combo with radiation. Moreover, WSD0628 shows low PK variation liability without aldehyde oxidase (AO) metabolism, low hERG liability ( >30 uM), and good safety window based on DRF studies. Taken together, our data provide a good rationale for WSD0628 to be developed toward clinic combo with radiation for the treatment of patients with GBM and cancers with CNS metastasis.

scholarly journals Heme oxygenase-1 and carbon monoxide modulate DNA repair through ataxia-telangiectasia mutated (ATM) protein

2011 ◽  
Vol 108 (35) ◽  
pp. 14491-14496 ◽  
Author(s):  
L. E. Otterbein ◽  
A. Hedblom ◽  
C. Harris ◽  
E. Csizmadia ◽  
D. Gallo ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Dna Repair ◽  
Heme Oxygenase ◽  
Ataxia Telangiectasia ◽  
Heme Oxygenase 1 ◽  
Ataxia Telangiectasia Mutated ◽  
Atm Protein

scholarly journals Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks

2006 ◽  
Vol 173 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Simon Bekker-Jensen ◽  
Claudia Lukas ◽  
Risa Kitagawa ◽  
Fredrik Melander ◽  
Michael B. Kastan ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Protein A ◽  
Dna Strand Breaks ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Interacting Protein ◽  
Atm Kinase ◽  
Strand Breaks ◽  
Dna Strand

We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by γ-H2AX is occupied by ataxia telangiectasia–mutated (ATM) kinase, Mdc1, and 53BP1. In contrast, repair factors (Rad51, Rad52, BRCA2, and FANCD2), ATM and Rad-3–related (ATR) cascade (ATR, ATR interacting protein, and replication protein A), and the DNA clamp (Rad17 and -9) accumulate in subchromatin microcompartments delineated by single-stranded DNA (ssDNA). BRCA1 and the Mre11–Rad50–Nbs1 complex interact with both of these compartments. Importantly, some core DSB regulators do not form cytologically discernible foci. These are further subclassified to proteins that connect DSBs with the rest of the nucleus (Chk1 and -2), that assemble at unprocessed DSBs (DNA-PK/Ku70), and that exist on chromatin as preassembled complexes but become locally modified after DNA damage (Smc1/Smc3). Finally, checkpoint effectors such as p53 and Cdc25A do not accumulate at DSBs at all. We propose that subclassification of DSB regulators according to their residence sites provides a useful framework for understanding their involvement in diverse processes of genome surveillance.

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