The zinc fingers of human poly(ADP-ribose) polymerase are differentially required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other structures recognize intact DNA.

Ikejima, Miyoko; Noguchi, Shigeru; Yamashita, Rumiko; Ogura, Tsutomu; Sügimura, Takashi; Gill, D M; Misawa, Miwa

doi:10.1016/s0021-9258(18)45824-3

Cited by 215 publications

(33 citation statements)

References 29 publications

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“…We also detected elevated levels of poly(ADPribose) in dissociated Xrcc1 Nes-Cre hippocampal neurons, which we confirmed was the result of ongoing Parp activity. The presence of elevated poly(ADP-ribose) is consistent with the SSBR defect in Xrcc1 Nes-Cre mice, because the synthesis of this polymer is triggered by endogenous SSBs (Benjamin & Gill, 1980;Ikejima et al, 1990;Eustermann et al, 2015;Hanzlikova et al, 2018). Nevertheless, that the level of endogenous poly(ADP-ribose) was high enough to detect in Xrcc1 Nes-Cre brain slices was surprising, and is consistent with the idea discussed above that SSB levels are particularly elevated in brain.…”

Section: Discussionsupporting

confidence: 78%

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Komulainen

Rey

et al. 2021

EMBO Reports

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Defects in DNA single-strand break repair (SSBR) are linked with neurological dysfunction but the underlying mechanisms remain poorly understood. Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1 Nes-Cre ) results in lethal seizures and shortened lifespan. Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro. Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1 Nes-Cre mice is greatly extended. This is the first demonstration that lethal seizures can be triggered by aberrant Parp1 activity at unrepaired SSBs, highlighting PARP inhibition as a possible therapeutic approach in hereditary neurological disease.

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Section: Discussionsupporting

confidence: 78%

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Komulainen

Rey

et al. 2021

EMBO Reports

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“…39 ARTi induce sensitivity of mammalian cells to DSBs 40,41 and delayed DSBR, 42 indicating PARylation is required for resolution of this variety of DNA lesion. PARP1 interacts with and becomes activated by DSBs in vitro 8,43,44 and in vivo, 45 agents that induce base damage and strand breakage and exhibit delayed kinetics of SSB resolution. [16][17][18][19][20] More recently, residual PARylation observed in parp1 -/cells led to the identification of a second DNA damage responsive PARP (PARP2).…”

Section: Conservation Of Dna Repair and Arts In Dictyosteliummentioning

confidence: 99%

The role of ADP-ribosylation in regulating DNA double-strand break repair

et al. 2012

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ADP-ribosylation is the post translational modification of proteins catalysed by ADP-ribosyltransferases (ARTs). ADP-ribosylation has been implicated in a wide variety of cellular processes including cell growth and differentiation, apoptosis and transcriptional regulation. Perhaps the best characterised role, however, is in DNA repair and genome stability where ADP-ribosylation promotes resolution of DNA single strand breaks. Although ADP-ribosylation also occurs at DNA double strand breaks (DSBs), which ARTs catalyse this reaction and the molecular basis of how this modification regulates their repair remains a matter of debate. Here we review recent advances in our understanding of how ADP-ribosylation regulates DSB repair. Specifically, we highlight studies using the genetic model organism Dictyostelium, in addition to vertebrate cells that identify a third ART that accelerates DSB repair by non-homologous end-joining through promoting the interaction of repair factors with DNA lesions. The implications of these data with regards to how ADP-ribosylation regulates DNA repair and genome stability are discussed.

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“…The role of poly (ADP-ribose) polymerase-1 (PARP-1) in responding to DNA damage and genomic stability (Durkacz et al, 1980), maintenance of telomeres (Beneke et al, 2008), and the stability of the replication fork (Bryant et al, 2009) is well known. However, the transcriptional functions of PARP-1 that may relate to chromatin remodeling as a means to regulate DNA repair are unknown (Ikejima et al, 1990).…”

Section: Identification Of Parp Regulated Transcriptomic Signaturesmentioning

confidence: 99%

RNA Biological Characteristics at the Peak of Cell Death in Different Hereditary Retinal Degeneration Mutants

Wei

Feng

et al. 2021

Front. Genet.

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Purpose: The present work investigated changes in the gene expression, molecular mechanisms, and pathogenesis of inherited retinal degeneration (RD) in three different disease models, to identify predictive biomarkers for their varied phenotypes and to provide a better scientific basis for their diagnosis, treatment, and prevention.Methods: Differentially expressed genes (DEGs) between retinal tissue from RD mouse models obtained during the photoreceptor cell death peak period (Pde6brd1 at post-natal (PN) day 13, Pde6brd10 at PN23, Prphrd2 at PN29) and retinal tissue from C3H wild-type mice were identified using Illumina high-throughput RNA-sequencing. Co-expression gene modules were identified using a combination of GO and KEGG enrichment analyses and gene co-expression network analysis. CircRNA-miRNA-mRNA network interactions were studied by genome-wide circRNA screening.Results:Pde6brd1, Pde6brd10, and Prphrd2 mice had 1,926, 3,096, and 375 DEGs, respectively. Genes related to ion channels, stress, inflammatory processes, tumor necrosis factor (TNF) production, and microglial cell activation were up-regulated, while genes related to endoplasmic reticulum regulation, metabolism, and homeostasis were down-regulated. Differential expression of transcription factors and non-coding RNAs generally implicated in other human diseases was detected (e.g., glaucoma, diabetic retinopathy, and inherited retinal degeneration). CircRNA-miRNA-mRNA network analysis indicated that these factors may be involved in photoreceptor cell death. Moreover, excessive cGMP accumulation causes photoreceptor cell death, and cGMP-related genes were generally affected by different pathogenic gene mutations.Conclusion: We screened genes and pathways related to photoreceptor cell death. Additionally, up-stream regulatory factors, such as transcription factors and non-coding RNA and their interaction networks were analyzed. Furthermore, RNAs involved in RD were functionally annotated. Overall, this study lays a foundation for future studies on photoreceptor cell death mechanisms.

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The zinc fingers of human poly(ADP-ribose) polymerase are differentially required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other structures recognize intact DNA.

Cited by 215 publications

References 29 publications

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures

The role of ADP-ribosylation in regulating DNA double-strand break repair

RNA Biological Characteristics at the Peak of Cell Death in Different Hereditary Retinal Degeneration Mutants

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