Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

Bourseguin, Julie; Cheng, Wen; Talbot, Emily; Hardy, Liana; Lai, Jenny; Jeffries, Ailsa M.; Lodato, Michael A.; Lee, Eunjung Alice; Khoronenkova, Svetlana V.

doi:10.1093/nar/gkac104

Cited by 24 publications

(16 citation statements)

References 92 publications

(124 reference statements)

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“…KU-60019 had virtually no effect on the survival of either OPCs (NG2 + ) or total OLs (Olig2 + ). Inhibition of ATM activity increases DNA damage by slowing down genomic repair (Bourseguin et al, 2022; Chow et al, 2019a; Mehta and Haber, 2014; Woodbine et al, 2011). We confirmed this in the Oli-Neu and OPC cultures by demonstrating a KU-60019-mediated, dose-dependent accumulation of 53BP1 + and γH2AX + foci (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We and others have demonstrated that when ATM activity is deficient, the reduced DNA repair capacity will often lead to DSB formation (Bourseguin et al, 2022; Chow et al, 2019a; Mehta and Haber, 2014). Precursors of OL express low levels of antioxidants and are thus poorly defended against oxidative stress (Back et al, 2002) and here we demonstrated that OPCs are also vulnerable to DSB formation.…”

Section: Discussionmentioning

confidence: 99%

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Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes

Tse

Cheng

et al. 2021

Preprint

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Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (Ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM mutations had been mapped by targeted genomic sequencing as well as samples from Atm-/- mice. In healthy human and wild type mouse cerebellum we confirmed the presence of ATM in white matter OLs. In A-T but not age-matched controls, a significant reduction in OL density was coupled with a massive astrogliosis. We found that the extent of this OL pathology was particularly strong in cases with frameshifts or premature termination ATM mutations. Similar pathologies were also found in Atm-/- mice in an age- and gene dose-dependent fashion. In vitro, DNA damage induced by etoposide-induced DSBs or blockade of ATM activity with KU-60019 differentially jeopardized cell cycle control in OL progenitors and mature OLs. Turning to structural analysis in silico, we identified likely interactions between ATM and myelin basic protein as well as myelin regulatory factor and confirm this by immunoprecipitation. These novel OL-specific functions of the ATM protein affect all stages of the OL lineage. They thus provide a cell biological basis for a direct role for ATM in central nervous system myelination and illustrate how the myelin pathology found in A-T is at least in part independent of neuronal degeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes

Tse

Cheng

et al. 2021

Preprint

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“…Besides p53, NFκB signaling is a major element for transcriptional reprogramming in response to DNA damage (51). DNA damage results in nuclear RelB enrichment and processing of p100 into p52, indicating a role also for the noncanonical NFκB pathway (51,52). While SLFN11 is an established marker for sensitivity to DDA-mediated cancer cell killing, its role as a repressor of NFκB2 mediated transcription may complicate targeted approaches aiming to activate SLFN11 in GBM.…”

Section: Discussionmentioning

confidence: 99%

SLFN11 Negatively Regulates Noncanonical NFκB Signaling to Promote Glioblastoma Progression

Fischietti

Eckerdt

Perez

et al. 2022

Cancer Research Communications

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Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular and tumor biology of GBM. CRISPR/Cas9 mediated knockout (KO) of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2 and CD44. Loss of SLFN11 stimulated expression of NF-kB target genes, consistent with a negative regulatory role for SLFN11 on the NF-kB pathway. Further, our studies identify p21 as a direct transcriptional target of NF-kB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.

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“…Activated microglia can exacerbate neurodegeneration by creating a cytotoxic environment for neurons, yet the specific factors contributing to microglia activation are not well understood [ 129 , 130 ]. It has been shown that DNA damage can activate microglia and lead to the secretion of pro-inflammatory cytokines, causing severe damage to neuronal cells [ 131 , 132 , 133 ]. This phenotype is primarily induced by activation of the damaged DNA-driven cGAS–STING signaling pathway, which is thought to initiate germ-free inflammation through both type-I interferon and NF-κB signaling [ 131 , 133 ].…”

Section: Mechanisms Of Dna Damage-mediated Neurotoxicity In Pdmentioning

confidence: 99%

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

Wang

et al. 2023

IJMS

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Parkinson’s disease (PD) is the second most common neurodegenerative disease around the world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in the pathophysiology of PD. There is growing evidence suggesting that DNA damage is involved in the propagation of cellular damage in PD, leading to neuropathology under different conditions. Here, we reviewed the current work on DNA damage repair in PD. First, we outlined the evidence and causes of DNA damage in PD. Second, we described the potential pathways by which DNA damage mediates neurotoxicity in PD and discussed the precise mechanisms that drive these processes by DNA damage. In addition, we looked ahead to the potential interventions targeting DNA damage and repair. Finally, based on the current status of research, key problems that need to be addressed in future research were proposed.

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Persistent DNA damage associated with ATM kinase deficiency promotes microglial dysfunction

Cited by 24 publications

References 92 publications

Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes

Myelin pathology in ataxia-telangiectasia is the cell autonomous effect of ATM deficiency in oligodendrocytes

SLFN11 Negatively Regulates Noncanonical NFκB Signaling to Promote Glioblastoma Progression

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

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