scholarly journals Ataxia telangiectasia mutated activation by transcription‐ and topoisomerase I‐induced DNA double‐strand breaks

EMBO Reports ◽  
2009 ◽  
Vol 10 (8) ◽  
pp. 887-893 ◽  
Author(s):  
Olivier Sordet ◽  
Christophe E Redon ◽  
Josée Guirouilh‐Barbat ◽  
Susan Smith ◽  
Stéphanie Solier ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Topoisomerase I ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Strand Breaks

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 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 H2AX regulates meiotic telomere clustering

2003 ◽  
Vol 163 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Oscar Fernandez-Capetillo ◽  
Bodo Liebe ◽  
Harry Scherthan ◽  
André Nussenzweig
Keyword(s):  
Ataxia Telangiectasia ◽  
Essential Role ◽  
Double Strand Breaks ◽  
Telomere Maintenance ◽  
Histone H2a ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Strand Breaks ◽  
Downstream Effector ◽  
Chromosome Fusions

The histone H2A variant H2AX is phosphorylated in response to DNA double-strand breaks originating from diverse origins, including dysfunctional telomeres. Here, we show that normal mitotic telomere maintenance does not require H2AX. Moreover, H2AX is dispensable for the chromosome fusions arising from either critically shortened or deprotected telomeres. However, H2AX has an essential role in controlling the proper topological distribution of telomeres during meiotic prophase I. Our results suggest that H2AX is a downstream effector of the ataxia telangiectasia–mutated kinase in controlling telomere movement during meiosis.

scholarly journals ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification

2010 ◽  
Vol 207 (7) ◽  
pp. 1369-1380 ◽  
Author(s):  
Shan Zha ◽  
Craig H. Bassing ◽  
Takaomi Sanda ◽  
James W. Brush ◽  
Harin Patel ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
Ataxia Telangiectasia ◽  
Cell Receptor ◽  
Large Deletion ◽  
Double Strand Breaks ◽  
Chromosome 12 ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Chromosome 14 ◽  
Strand Breaks

Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor α/δ (Tcra/d) locus. Such translocations have been thought to result from aberrant repair of DNA double-strand breaks (DSBs) during Tcra locus V(D)J recombination, and to require the Tcra enhancer (Eα) for Tcra rearrangement or expression of the translocated oncogene. We now show that, in addition to the known chromosome 14 translocation, ATM-deficient mouse thymic lymphomas routinely contain a centromeric fragment of chromosome 14 that spans up to the 5′ boundary of the Tcra/d locus, at which position a 500-kb or larger region centromeric to Tcra/d is routinely amplified. In addition, they routinely contain a large deletion of the telomeric end of one copy of chromosome 12. In contrast to prior expectations, the recurrent translocations and amplifications involve V(D)J recombination–initiated breaks in the Tcrd locus, as opposed to the Tcra locus, and arise independently of the Eα. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells.

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