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 Activation of p38 MAP kinase by DNA double-strand breaks in V(D)J recombination induces a G2/M cell cycle checkpoint

2006 ◽  
Vol 25 (4) ◽  
pp. 763-773 ◽  
Author(s):  
Gustavo Pedraza-Alva ◽  
Miroslav Koulnis ◽  
Colette Charland ◽  
Tina Thornton ◽  
James L Clements ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Map Kinase ◽  
P38 Map Kinase ◽  
Cell Cycle Checkpoint ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
M Cell ◽  
Strand Breaks ◽  
Cycle Checkpoint

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 Ionizing Radiation–dependent γ-H2AX Focus Formation Requires Ataxia Telangiectasia Mutated and Ataxia Telangiectasia Mutated and Rad3-related

2005 ◽  
Vol 16 (5) ◽  
pp. 2566-2576 ◽  
Author(s):  
Joanna D. Friesner ◽  
Bo Liu ◽  
Kevin Culligan ◽  
Anne B. Britt
Keyword(s):  
Ionizing Radiation ◽  
Ataxia Telangiectasia ◽  
Double Strand Breaks ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Focus Formation ◽  
Strand Breaks ◽  
M Phase ◽  
Stalled Replication Forks

The histone variant H2AX is rapidly phosphorylated at the sites of DNA double-strand breaks (DSBs). This phosphorylated H2AX (γ-H2AX) is involved in the retention of repair and signaling factor complexes at sites of DNA damage. The dependency of this phosphorylation on the various PI3K-related protein kinases (in mammals, ataxia telangiectasia mutated and Rad3-related [ATR], ataxia telangiectasia mutated [ATM], and DNA-PKCs) has been a subject of debate; it has been suggested that ATM is required for the induction of foci at DSBs, whereas ATR is involved in the recognition of stalled replication forks. In this study, using Arabidopsis as a model system, we investigated the ATR and ATM dependency of the formation of γ-H2AX foci in M-phase cells exposed to ionizing radiation (IR). We find that although the majority of these foci are ATM-dependent, ∼10% of IR-induced γ-H2AX foci require, instead, functional ATR. This indicates that even in the absence of DNA replication, a distinct subset of IR-induced damage is recognized by ATR. In addition, we find that in plants, γ-H2AX foci are induced at only one-third the rate observed in yeasts and mammals. This result may partly account for the relatively high radioresistance of plants versus yeast and mammals.

scholarly journals 53BP1 is required for class switch recombination

2004 ◽  
Vol 165 (4) ◽  
pp. 459-464 ◽  
Author(s):  
Irene M. Ward ◽  
Bernardo Reina-San-Martin ◽  
Alexandru Olaru ◽  
Kay Minn ◽  
Koji Tamada ◽  
...  
Keyword(s):  
Class Switch Recombination ◽  
Cell Cycle Checkpoint ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Checkpoint Control ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Strand Breaks ◽  
Class Switch ◽  
Cycle Checkpoint

53BP1 participates early in the DNA damage response and is involved in cell cycle checkpoint control. Moreover, the phenotype of mice and cells deficient in 53BP1 suggests a defect in DNA repair (Ward et al., 2003b). Therefore, we asked whether or not 53BP1 would be required for the efficient repair of DNA double strand breaks. Our data indicate that homologous recombination by gene conversion does not depend on 53BP1. Moreover, 53BP1-deficient mice support normal V(D)J recombination, indicating that 53BP1 is not required for “classic” nonhomologous end joining. However, class switch recombination is severely impaired in the absence of 53BP1, suggesting that 53BP1 facilitates DNA end joining in a way that is not required or redundant for the efficient closing of RAG-induced strand breaks. These findings are similar to those observed in mice or cells deficient in the tumor suppressors ATM and H2AX, further suggesting that the functions of ATM, H2AX, and 53BP1 are closely linked.

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