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Review
. 2021 Aug 31;12(9):1370.
doi: 10.3390/genes12091370.

ATM's Role in the Repair of DNA Double-Strand Breaks

Atsushi Shibata  1 , Penny A Jeggo  2
Affiliations
Review

ATM's Role in the Repair of DNA Double-Strand Breaks

Atsushi Shibata et al. Genes (Basel). .

Abstract

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.

Keywords: ATM; DNA double-strand break; homologous recombination; ionizing radiation; non-homologous end joining.

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Conflict of interest statement

The authors declare that there are no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
ATM activation after DSB formation. (A) ATM structure is associated with the kinase activity. The monomeric form has greater kinase activity than the dimeric form. (B) A two-dimensional ATM structure with some of ATM’s relevant domains indicated.
Figure 2
Figure 2
ATM activation at DSB sites. ATM phosphorylates H2AX at S139, this, in turn, promotes the recruitment of MDC1, which, in its own turn, facilitates the RNF8/RNF168-dependent ubiquitination of H2AX at K15. These signals recruit 53BP1 to form nano domains, which are visualized as nano foci. ATM-dependent post-translational modifications are shown in the bottom panel. The interacting proteins and downstream effectors are described in more detail in the text. CTCF: CCCTC-Binding Factor.
Figure 3
Figure 3
DSB repair kinetics after <1–5 Gy. (A) DSB repair kinetics in G1 phase. (B) An example of repair kinetics in defective NHEJ or ATM-related factors is shown. (C) DSB repair kinetics in G2 phase. (D) An example of repair kinetics in defective NHEJ, HR, or ATM-related factors is shown.
Figure 4
Figure 4
Roles of ATM during DSB end resection in G2 phase. See the text for details.
Figure 5
Figure 5
Summary highlighting the 4 pathways discussed in the text by which ATM influences the repair of DSBs. The impact on the level or fidelity of DSB repair in each pathway is shown by brackets; the type of cell affected is highlighted in red. Additional impacts of ATM, such as its role in regulating apoptosis, may also influence survival levels in response to DSBs but here we focus on pathways that influence DSB repair.
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