scholarly journals Emerging Perspectives on DNA Double-strand Breaks in Neurodegenerative Diseases

2019 ◽  
Vol 17 (12) ◽  
pp. 1146-1157
Author(s):  
Ling-Shuang Zhu ◽  
Ding-Qi Wang ◽  
Ke Cui ◽  
Dan Liu ◽  
Ling-Qiang Zhu
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Ataxia Telangiectasia ◽  
Double Strand Breaks ◽  
Human Beings ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Physiological Processes ◽  
Underlying Mechanisms ◽  
Lateral Sclerosis

DNA double-strand breaks (DSBs) are common events that were recognized as one of the most toxic lesions in eukaryotic cells. DSBs are widely involved in many physiological processes such as V(D)J recombination, meiotic recombination, DNA replication and transcription. Deregulation of DSBs has been reported in multiple diseases in human beings, such as the neurodegenerative diseases, with which the underlying mechanisms are needed to be illustrated. Here, we reviewed the recent insights into the dysfunction of DSB formation and repair, contributing to the pathogenesis of neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and ataxia telangiectasia (A-T).

scholarly journals Requirement of ATM in Phosphorylation of the Human p53 Protein at Serine 15 following DNA Double-Strand Breaks

1999 ◽  
Vol 19 (4) ◽  
pp. 2828-2834 ◽  
Author(s):  
Kazumi Nakagawa ◽  
Yoichi Taya ◽  
Katsuyuki Tamai ◽  
Masaru Yamaizumi
Keyword(s):  
Heat Shock ◽  
Ataxia Telangiectasia ◽  
Xeroderma Pigmentosum ◽  
P53 Protein ◽  
Double Strand Breaks ◽  
Nuclear Accumulation ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Absolute Requirement ◽  
Primary Fibroblasts

ABSTRACT Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.

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 CHTF18 ensures the quantity and quality of the ovarian reserve†

2020 ◽  
Vol 103 (1) ◽  
pp. 24-35
Author(s):  
Rebecca A Holton ◽  
Abigail M Harris ◽  
Barenya Mukerji ◽  
Tanu Singh ◽  
Ferdusy Dia ◽  
...  
Keyword(s):  
Ovarian Follicle ◽  
Reproductive Potential ◽  
Oocyte Quality ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Chromosome Transmission ◽  
Underlying Mechanisms ◽  
Factor C

Abstract The number and quality of oocytes, as well as the decline in both of these parameters with age, determines reproductive potential in women. However, the underlying mechanisms of this diminution are incompletely understood. Previously, we identified novel roles for CHTF18 (Chromosome Transmission Fidelity Factor 18), a component of the conserved Replication Factor C-like complex, in male fertility and gametogenesis. Currently, we reveal crucial roles for CHTF18 in female meiosis and oocyte development. Chtf18−/− female mice are subfertile and have fewer offspring beginning at 6 months of age. Consistent with age-dependent subfertility, Chtf18−/− ovaries contain fewer follicles at all stages of folliculogenesis than wild type ovaries, but the decreases are more significant at 3 and 6 months of age. By 6 months of age, both primordial and growing ovarian follicle pools are markedly reduced to near depletion. Chromosomal synapsis in Chtf18−/− oocytes is complete, but meiotic recombination is impaired resulting in persistent DNA double-strand breaks, fewer crossovers, and early homolog disjunction during meiosis I. Consistent with poor oocyte quality, the majority of Chtf18−/− oocytes fail to progress to metaphase II following meiotic resumption and a significant percentage of those that do progress are aneuploid. Collectively, our findings indicate critical functions for CHTF18 in ensuring both the quantity and quality of the mammalian oocyte pool.

scholarly journals DNA double-strand breaks: a potential therapeutic target for neurodegenerative diseases

2019 ◽  
Vol 27 (4) ◽  
pp. 345-364 ◽  
Author(s):  
Nidheesh Thadathil ◽  
Roderick Hori ◽  
Jianfeng Xiao ◽  
Mohammad Moshahid Khan
Keyword(s):  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Potential Therapeutic Target ◽  
Strand Breaks

scholarly journals Lessons from the meiotic recombination landscape of the ZMM deficient budding yeast Lachancea waltii

2021 ◽  
Author(s):  
Fabien Dutreux ◽  
Abhishek Dutta ◽  
Emilien Peltier ◽  
Sabrina Bibi-Triki ◽  
Anne Friedrich ◽  
...  
Keyword(s):  
Meiotic Recombination ◽  
Budding Yeast ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Yeast Saccharomyces Cerevisiae ◽  
Strand Breaks ◽  
Crossover Interference ◽  
Recombination Hotspots ◽  
Elevated Frequency ◽  
Underlying Mechanisms

Meiotic recombination has been deeply characterized in a few model species only, notably in the budding yeast Saccharomyces cerevisiae. Interestingly, most members of the ZMM pathway that implements meiotic crossover interference in S. cerevisiae have been lost in Lachancea yeast species after the divergence of Lachancea kluyveri from the rest of the clade. This suggests major differences in the control of crossover distribution. After investigating meiosis in L. kluyveri, we determined the meiotic recombination landscape of Lachancea waltii and identified several characteristics that should help understand better the underlying mechanisms. Such characteristics include systematic regions of loss of heterozygosity (LOH) in L. waltii hybrids, compatible with dysregulated Spo11-mediated DNA double strand breaks (DSB) independently of meiosis. They include a higher recombination rate in L. waltii than in L. kluyveri despite the lack of multiple ZMM pro-crossover factors. L. waltii exhibits an elevated frequency of zero-crossover bivalents as L. kluyveri but opposite to S. cerevisiae. L. waltii gene conversion tracts lengths are comparable to those observed in S. cerevisiae and shorter than in L. kluyveri despite the lack of Mlh2, a factor limiting conversion tracts size in S. cerevisiae. L. waltii recombination hotspots are not shared with either S. cerevisiae or L. kluyveri, showing that meiotic recombination hotspots can evolve at a rather limited evolutionary scale within budding yeasts. Finally, in line with the loss of several ZMM genes, we found only residual crossover interference in L. waltii likely coming from the modest interference existing between recombination precursors.

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.

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