The DNA double-strand break response in the nervous system

Abner, Clint W.; McKinnon, Peter J.

doi:10.1016/j.dnarep.2004.03.009

Cited by 59 publications

(33 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, however, this observation does not exclude an ongoing role of the ATM protein in Purkinje neurons at later stages (see [27]). In humans, Purkinje neuron differentiation extends from the late fetal period into the first year of life [28].…”

Section: Discussionmentioning

confidence: 87%

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

et al. 2007

View full text Add to dashboard Cite

The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT-like disorder.

show abstract

Section: Discussionmentioning

confidence: 87%

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Their finite number, long life, high metabolic rate, and continuous exposure to oxidative stress on the one hand, and extensive gene transcription on the other hand, call for stringent control of genomic integrity. It is not surprising that defects in various branches of the DNA damage response lead to severe neurological demise (75)(76)(77)(78). In this regard, Atm-knock-out mice were an unexpected exception: while exhibiting most of the characteristics of human A-T, they barely show the cerebellar degeneration and associated neuromotor dysfunction (79 -81).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Ataxia-Telangiectasia Mutated (ATM) Mediates the Cellular Response to DNA Double Strand Breaks in Human Neuron-like Cells

Biton

Dar

Mittelman

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

The protein kinase ATM (ataxia-telangiectasia mutated) activates the cellular response to double strand breaks (DSBs), a highly cytotoxic DNA lesion. ATM is activated by DSBs and in turn phosphorylates key players in numerous damage response pathways. ATM is missing or inactivated in the autosomal recessive disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, genomic instability, radiation sensitivity, and cancer predisposition. The predominant symptom of A-T is a progressive loss of movement coordination due to ongoing degeneration of the cerebellar cortex and peripheral neuropathy. A major deficiency in understanding A-T is the lack of information on the role of ATM in neurons. It is unclear whether the ATM-mediated DSB response operates in these cells similarly to proliferating cells. Furthermore, ATM was reported to be cytoplasmic in neurons and suggested to function in these cells in capacities other than the DNA damage response. Recently we obtained genetic molecular evidence that the neuronal degeneration in A-T does result from defective DNA damage response. We therefore undertook to investigate this response in a model system of human neuron-like cells (NLCs) obtained by neuronal differentiation in culture. ATM was largely nuclear in NLCs, and their ATM-mediated responses to DSBs were similar to those of proliferating cells. Knocking down ATM did not interfere with neuronal differentiation but abolished ATM-mediated damage responses in NLCs. We concluded that nuclear ATM mediates the DSB response in NLCs similarly to in proliferating cells. Attempts to understand the neurodegeneration in A-T should be directed to investigating the DSB response in the nervous system.

show abstract

“…Regarding the latter issue, based on their studies using Atm −/− mice [36,37] McKinnon and co-workers proposed a model in which ATM acts at a stage just after terminal differentiation to trigger apoptosis of neurons that have experienced excess DNA damage during brain development. According to this model, in the absence of ATM, such neurons survive and populate the Purkinje neuron layer, only to degenerate later as a result of DNA damage experienced during development [38]. However, it is entirely possible that ATM plays both a proapoptotic role just after terminal differentiation, as in the McKinnon hypothesis, as well as an ongoing role in the detection of DNA damage, and that the final neurological phenotype of AT patients is due to the loss of both pathways.…”

Section: Caveatsmentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

View full text Add to dashboard Cite

The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

show abstract

The DNA double-strand break response in the nervous system

Cited by 59 publications

References 61 publications

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain

Nuclear Ataxia-Telangiectasia Mutated (ATM) Mediates the Cellular Response to DNA Double Strand Breaks in Human Neuron-like Cells

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Contact Info

Product

Resources

About