Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, Lukashchuk V, Chiang SC, Ray S, Mulcahy PJ, Jurga M, Tsagakis I, Iannitti T, Chandran J, Coldicott I, De Vos KJ, Hassan MK, Higginbottom A, Shaw PJ, Hautbergue GM, Azzouz M, El-Khamisy SF. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017 Sep;20(9):1225-1235. Epub 2017 Jul 17 PubMed.
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Picower Institute of MIT
This study is consistent with our previous work on the relationship of accumulation of DNA damage and neurodegeneration. In our paper published in 2013 in Nature Neuroscience (Wang et al.), we showed that the familial ALS gene product, FUS, a DNA/RNA binding protein, is recruited to DNA double-strand break (DSB) sites and is necessary for efficient DNA repair. Thus, the findings of the current paper that demonstrate C9ORF72 impacts DNA repair are very consistent with ours, and together make a strong argument for the role of unrepaired DNA breaks in ALS.
The one surprising finding in the current paper is that C9ORF72 repeats impair ATM activity, but increase the γH2AX signal. This is perplexing, as ATM is the key kinase that phosphorylates the histone 2A variant and creates the amplified γH2AX signal, although another member of the PI3 kinase family, DNA-PK, can also phosphorylate H2AX in post-mitotic cells such as neurons. γH2AX is known to facilitate the recruitment of DNA repair machinery to the break sites.
In our 2013 Wang et al. study, we showed that FUS loss of function caused considerable reduction in ATM activity and decreased γH2AX signal at break sites. Therefore, I am curious to know how reduced ATM activity can result in increased phosphorylation of its substrate(s), and whether DNA-PK activity compensates for the reduction in activated ATM in the context of C9ORF72 overexpression.
References:
Wang WY, Pan L, Su SC, Quinn EJ, Sasaki M, Jimenez JC, Mackenzie IR, Huang EJ, Tsai LH. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013 Oct;16(10):1383-91. PubMed.
View all comments by Li-Huei TsaiUniversity of Sheffield
I agree with Li-Huei Tsai; we were surprised too. As rightly indicated, H2AX can become phosphorylated by other nervous system kinases, such as DNA-PK, which could compensate in the absence of efficient DNA repair signalling by ATM in the context of C9ORF72 overexpression.
It should be noted that the defect we report here is in the sustained non-canonical activation of ATM signalling cascade due to inefficient H2A ubiquitylation and 53BP1 recruitment, which also correlates with reduced phosphorylation of other ATM substrates such as p53 and KAP1.
The study by Li-Huei Tsai's group back in 2013 was instrumental in setting the scene for the connection between ALS and DNA repair. Our current study reiterates this important link but also highlights important mechanistic differences by which ALS mutants impact DNA repair capacity in the nervous system.
View all comments by Sherif El-KhamisyUniversity of Queensland
It is well established that DNA double-strand breaks and R-loops contribute to genome instability and, in turn, to pathological outcomes. What is novel about this study is that a mechanism is provided, bringing together both R-loops and DNA double-strand breaks, in explaining how a short DNA sequence, when expanded, causes two major neurodegenerative diseases, ALS and dementia.
It is also of considerable interest that this is demonstrated in both human and animal model systems. Furthermore, ATM, the protein defective in another human neurodegenerative disease, Ataxia-Telangiectasia (A-T), is impaired in its function in this system. These findings provide potential approaches to developing new therapeutic possibilities for intervention in these disorders.
View all comments by Martin LavinMake a Comment
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