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

Gorodetsky, Elena; Calkins, Sarah; Ahn, Julia; Brooks, Philip J.

doi:10.1016/j.dnarep.2007.06.011

Cited by 28 publications

(20 citation statements)

References 39 publications

(50 reference statements)

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“…In Tuj1-positive neurons, pS/TQ foci also formed upon irradiation, their intensity being comparable to that in NSC (Figure 5a, lower panel and Supplementary Figure S9B). We conclude that, differently from astrocytes, and consistently with previous reports, 22,23 neurons do activate canonical DDR upon DNA damage, thus highlighting the unique peculiarity of astrocytes.…”

Section: Resultssupporting

confidence: 66%

Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency

2011

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The impact and consequences of damage generation into genomic DNA, especially in the form of DNA double-strand breaks, and of the DNA-damage response (DDR) pathways that are promptly activated, have been elucidated in great detail. Most of this research, however, has been performed on proliferating, often cancerous, cell lines. In a mammalian body, the majority of cells are terminally differentiated (TD), and derives from a small pool of self-renewing somatic stem cells. Here, we comparatively studied DDR signaling and radiosensitivity in neural stem cells (NSC) and their TD-descendants, astrocytes -the predominant cells in the mammalian brain. Astrocytes have important roles in brain physiology, development and plasticity. We discovered that NSC activate canonical DDR upon exposure to ionizing radiation. Strikingly, astrocytes proved radioresistant, lacked functional DDR signaling, with key DDR genes such as ATM being repressed at the transcriptional level. Nevertheless, astrocytes retain the expression of non-homologous end-joining (NHEJ) genes and indeed they are DNA repair proficient. Unlike in NSC, in astrocytes DNA-PK seems to be the PI3K-like protein kinase responsible for cH2AX signal generation upon DNA damage. We also demonstrate the lack of functional DDR signaling activation in vivo in astrocytes of irradiated adult mouse brains, although adjacent neurons activate the DDR.

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Section: Resultssupporting

confidence: 66%

Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency

2011

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“…In addition to these findings in mice, we [35] showed that the ATM protein is predominantly localized to the nucleus of Purkinje neurons in postmortem human brain. Importantly, in contrast to the earlier publication [30], we used postmortem brain tissue from AT patients to demonstrate the specificity of the ATM antibody.…”

Section: Caveatsmentioning

confidence: 81%

“…Having said this, there are important outstanding issues that remain, concerning what type of DNA damage is sensed by ATM in neurons [35], and at what stage of Purkinje cell development the ATM protein functions. 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.…”

Section: Caveatsmentioning

confidence: 99%

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

2008

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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.

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“…This was particularly evident in the cortex and by the atrophy of the anterior commissure. Previous analysis of human CS-B and mouse Cs-b concentrated on the Purkinje layer in the cerebellum that appears to be a major site of degeneration (5,46). This layer has elevated p53 and shows accumulation of the DNA damage markers ATM and Mre11 (5,46).…”

Section: Discussionmentioning

confidence: 99%

Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome

Revet¹,

Feeney²,

Tang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cockayne syndrome (CS) is a rare autosomal recessive neurodegenerative disease that is associated with mutations in either of two transcription-coupled DNA repair genes, CSA or CSB. oligodendrocytes were unable to generate sufficient MBP or to maintain the proper myelination during early development. Csb is a multifunctional protein regulating both repair and the transcriptional response to reactive oxygen through its interaction with histone acetylase p300 and the hypoxia-inducible factor (HIF)1 pathway. On the basis of our results, combined with that of others, we suggest that in Csb the transcriptional response predominates during early development, whereas a neurodegenerative response associated with repair deficits predominates in later life.transcription-coupled repair | behavior | rotenone | γH2Ax

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

Cited by 28 publications

References 39 publications

Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency

Terminally differentiated astrocytes lack DNA damage response signaling and are radioresistant but retain DNA repair proficiency

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

Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome

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