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

Schneider, L; Fumagalli, Marzia; Fagagna, Fabrizio d’Adda di

doi:10.1038/cdd.2011.129

Cited by 61 publications

(78 citation statements)

References 41 publications

(57 reference statements)

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“…26 Taken together our results bring to light a significant difference in the way soma and immortal germline cope with DNA damage and may indicate the possibility that such distinction could be extended to other important cellular processes.…”

Section: Discussionmentioning

confidence: 91%

Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans

et al. 2012

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The germline of Caenorhabditis elegans is a well-established model for DNA damage response (DDR) studies. However, the molecular basis of the observed cell death resistance in the soma of these animals remains unknown. We established a set of techniques to study ionizing radiation-induced DNA damage generation and DDR activation in a whole intact worm. Our singlecell analyses reveal that, although germline and somatic cells show similar levels of inflicted DNA damage, somatic cells, differently from germline cells, do not activate the crucial apical DDR kinase ataxia-telengiectasia mutated (ATM). We also show that DDR signaling proteins are undetectable in all somatic cells and this is due to transcriptional repression. However, DNA repair genes are expressed and somatic cells retain the ability to efficiently repair DNA damage. Finally, we demonstrate that germline cells, when induced to transdifferentiate into somatic cells within the gonad, lose the ability to activate ATM. Overall, these observations provide a molecular mechanism for the known, but hitherto unexplained, resistance to DNA damage-induced cell death in C. elegans somatic cells. We propose that the observed lack of signaling and cell death but retention of DNA repair functions in the soma is a Caenorhabditis-specific evolutionary-selected strategy to cope with its lack of adult somatic stem cell pools and regenerative capacity.

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Section: Discussionmentioning

confidence: 91%

Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans

et al. 2012

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“…In contrast, TDP1 +/+ and TDP1 −/− murine astrocytes showed little difference λH2AX focus formation in response to H 2 O 2 , camptothecin or ionizing radiation (69). It has been reported that mouse astrocytes are radioresistant with reduced levels of ATM, and lack 53BP1 focus formation following exposure to ionizing radiation (73). 53BP1 plays an important role in preventing DNA end resection and promoting NHEJ (74) and the unusual behavior of 53BP1 in murine astrocytes suggests that DSB repair may be unconventional in this cell type.…”

Section: Discussionmentioning

confidence: 99%

TDP1 promotes assembly of non-homologous end joining protein complexes on DNA

Heo

Summerlin

et al. 2015

DNA Repair

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The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. In tumor cells, the ability to repair DSBs predicts response to radiation and many cytotoxic anti-cancer drugs. DSB repair pathways include homologous recombination and non-homologous end joining (NHEJ). NHEJ is a template-independent mechanism, yet many NHEJ repair products carry limited genetic changes, which suggests that NHEJ includes mechanisms to minimize error. Proteins required for mammalian NHEJ include Ku70/80, the DNA-dependent protein kinase (DNA-PKcs), XLF/Cernunnos and the XRCC4:DNA ligase IV complex. NHEJ also utilizes accessory proteins that include DNA polymerases, nucleases, and other end-processing factors. In yeast, mutations of tyrosyl-DNA phosphodiesterase (TDP1) reduced NHEJ fidelity. TDP1 plays an important role in repair of topoisomerase-mediated DNA damage and 3′-blocking DNA lesions, and mutation of the human TDP1 gene results in an inherited human neuropathy termed SCAN1. We found that human TDP1 stimulated DNA binding by XLF and physically interacted with XLF to form TDP1:XLF:DNA complexes. TDP1:XLF interactions preferentially stimulated TDP1 activity on dsDNA as compared to ssDNA. TDP1 also promoted DNA binding by Ku70/80 and stimulated DNA-PK activity. Because Ku70/80 and XLF are the first factors recruited to the DSB at the onset of NHEJ, our data suggest a role for TDP1 during the early stages of mammalian NHEJ.

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“…Stem cells from different organs have been proposed to be radiation resistant due to their highly effective mechanisms capable of repairing DNA damage [59–62]. Moreover, the radioresistance could also be attributed to the low dividing activity of the stem cells.…”

Section: Discussionmentioning

confidence: 99%

The Subventricular Zone Is Able to Respond to a Demyelinating Lesion After Localized Radiation

et al. 2014

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Radiation is a common tool in the treatment of brain tumors that induces neurological deficits as a side effect. Some of these deficits appear to be related to the impact of radiation on the neurogenic niches, producing a drastic decrease in the proliferative capacity of these regions. In the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles is the main neurogenic niche. Neural stem/precursor cells (NSCs) within the SVZ play an important role in brain repair following injuries. However, the irradiated NSCs' ability to respond to damage has not been previously elucidated. In this study, we evaluated the effects of localized radiation on the SVZ ability to respond to a lysolecithin-induced demyelination of the striatum. We demonstrated that the proliferation rate of the irradiated SVZ was increased after brain damage and that residual NSCs were reactivated. The irradiated SVZ had an expansion of doublecortin positive cells that appeared to migrate from the lateral ventricles toward the demyelinated striatum, where newly generated oligodendrocytes were found. In addition, in the absence of demyelinating damage, remaining cells in the irradiated SVZ appeared to repopulate the neurogenic niche a year post-radiation. These findings support the hypothesis that NSCs are radioresistant and can respond to a brain injury, recovering the neurogenic niche. A more complete understanding of the effects that localized radiation has on the SVZ may lead to improvement of the current protocols used in the radiotherapy of cancer.

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

Cited by 61 publications

References 41 publications

Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans

Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans

TDP1 promotes assembly of non-homologous end joining protein complexes on DNA

The Subventricular Zone Is Able to Respond to a Demyelinating Lesion After Localized Radiation

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