Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

Mabb, Angela M.; Simon, Jeremy M.; King, Ian; Lee, Hyeong-Min; An, L.; Philpot, Benjamin D.; Zylka, Mark J.

doi:10.1371/journal.pone.0156439

Cited by 38 publications

(46 citation statements)

References 52 publications

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“…Moreover, Ube3a expression was restored in the topotecan treated but not in the Top1 ‐deleted neurons. The data from these authors also suggest that topotecan inhibits topoisomerase type I by binding to both topoisomerase type I and DNA, forming a topoisomerase type I cleavage complex [Mabb et al, ]. These data raise the concern that the systemic use of topoisomerase inhibitors such as topotecan for the treatment of AS may result in unintended off‐target effects due to the repression of many different long genes and possibly over‐expression of the shorter genes [Plasschaert and Bartolomei, ].…”

Section: Resultsmentioning

confidence: 99%

Angelman syndrome: Current and emerging therapies in 2016

Tan¹,

Bird²

2016

American J of Med Genetics Pt C

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Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally-inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS) at the unmethylated paternal locus. We reviewed all published information on the clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies in AS. To date, all clinical trials that strove to improve neurodevelopment in AS have been unsuccessful. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of an 8-week open-label trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive, while a subsequent randomized placebo-controlled trial suggested that treatment with minocycline for 8 weeks did not result in any neurodevelopmental gains. A 1-year randomized placebo-controlled trial using levodopa to alter the phosphorylation of calcium/calmodulin-dependent kinase II did not lead to any improvement in neurodevelopment. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Artificial transcription factors are being developed to "super activate" UBE3A or inhibit UBE3A-AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more common complications of AS. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Angelman syndrome: Current and emerging therapies in 2016

Tan¹,

Bird²

2016

American J of Med Genetics Pt C

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“…Topotecan was identified as an upstream regulatory pathway because it inhibits the topoisomerases that long genes depend on for their transcription [202][203][204][205][206][207] . It follows that the genes most affected by topotecan administration are long genes, which have a clear overlap given the length of FMRP target mRNAs and the genes encoding them.…”

Section: Loss Of Function Of Fmrp Causes Altered Behavior and Cognitimentioning

confidence: 99%

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Driesche

Sawicka

Zhang

et al. 2019

Preprint

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Highlights 1. We have created a mouse model in which endogenous FMRP can be conditionally tagged.2. Using tag-specific CLIP we describe ranked and specific sets of in vivo FMRP mRNA targets in two types of neurons.3. This ranking was used to reveal that FMRP regulates mRNAs with long coding sequences.4. FMRP mRNA targets in Purkinje cells, including the top-ranked IP3 receptor, are related to cell-autonomous Fragile X phenotypes. 5.We have updated our previous list of whole mouse brain FMRP mRNA targets with more replicates, deeper sequencing and improved analysis 6. The use of tagged FMRP in less abundant cell populations allowed identification of novel mRNA targets missed in a whole brain analysis

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“…Recent studies suggest that transcriptional stress-driven DNA damage is also prevalent in postmitotic neurons and has the potential to disrupt genes that neurons depend on most 2 . We recently identified TOP1 as a key transcriptional regulator in postmitotic neurons 23,24 . TOP1 relieves DNA supercoiling generated during transcription by catalyzing a single-strand DNA cleavage 22 .…”

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confidence: 99%

Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration

et al. 2020

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Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD +) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted.

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Topoisomerase 1 Regulates Gene Expression in Neurons through Cleavage Complex-Dependent and -Independent Mechanisms

Cited by 38 publications

References 52 publications

Angelman syndrome: Current and emerging therapies in 2016

Angelman syndrome: Current and emerging therapies in 2016

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration

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