A possible link between nutritional uptake of ubiquitous topoisomerase inhibitors and autism?

Marko, Doris; Boege, Fritz

doi:10.1016/j.ijdevneu.2016.06.003

Cited by 4 publications

(5 citation statements)

References 18 publications

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“…Top2 poisons such as ETOP are mainstream anti-cancer drugs, and dietary uptake of Top2 poisons has been linked to human diseases such as infant leukemia and autism (Marko and Boege, 2016). Therefore, the Top2 poison defense mechanism discovered here has potential implications for disease etiology and treatment.…”

Section: Discussionmentioning

confidence: 93%

“…Some of them, such as flavonoids, are common and abundant secondary metabolites. Therefore, a wide range of organisms, including humans, are often exposed to Top2 poisons through contact or dietary consumption (Marko and Boege, 2016). The budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe, from which significant insights into Top2 poisons have been gleaned (Hartsuiker et al, 2009;Malik and Nitiss, 2004;Nitiss and Wang, 1988), co-inhabit with plants and soil microorganisms and hence likely have evolved mechanisms defending against Top2 poisons.…”

Section: Introductionmentioning

confidence: 99%

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SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage

Diao

et al. 2017

Molecular Cell

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The action of DNA topoisomerase II (Top2) creates transient DNA breaks that are normally concealed inside Top2-DNA covalent complexes. Top2 poisons, including ubiquitously present natural compounds and clinically used anti-cancer drugs, trap Top2-DNA complexes. Here, we show that cells actively prevent Top2 degradation to avoid the exposure of concealed DNA breaks. A genome-wide screen revealed that fission yeast cells lacking Rrp2, an Snf2-family DNA translocase, are strongly sensitive to Top2 poisons. Loss of Rrp2 enhances SUMOylation-dependent ubiquitination and degradation of Top2, which in turn increases DNA damage at sites where Top2-DNA complexes are trapped. Rrp2 possesses SUMO-binding ability and prevents excessive Top2 degradation by competing against the SUMO-targeted ubiquitin ligase (STUbL) for SUMO chain binding and by displacing SUMOylated Top2 from DNA. The budding yeast homolog of Rrp2, Uls1, plays a similar role, indicating that this genome protection mechanism is widely employed, a finding with implications for cancer treatment.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage

Diao

et al. 2017

Molecular Cell

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“…It is noteworthy that a number of known or suspected environmental risk factors of autism are Top2 inhibitors, such as bisphenol A ( 15 ), polychlorinated biphenyls ( 16 , 66 ), chlorpyrifos and chlorpyrifos oxon ( 17 ), and genistein ( 67 ). Top2 inhibitors are widely present in the environment, and their possible link to autism has previously been proposed ( 68 ). Chemicals with Top2-inhibiting activities that are present in the environment but have not yet been clearly associated with autism include flavonoids ( 69 ), alternariol ( 70 ), Ginkgo biloba leaf extract ( 71 ), and lignans ( 72 ), to name a few.…”

Section: Discussionmentioning

confidence: 99%

Top2a promotes the development of social behavior via PRC2 and H3K27me3

et al. 2022

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Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused defects in social interaction and communication, which are behaviors that relate to core symptoms of autism. Mutation of Top2a in zebrafish caused down-regulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets have binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation (H3K27me3). Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of the PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.

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“…As Top IIa/b inhibition by ICRF-193 produces a similar length-dependent transcriptional reduction, it is possible that Top II is also responsible for the regulation of certain autism-associated candidate genes [ 255 ]. Furthermore, it has been proposed that environmental and dietary sources of topoisomerase poisons and inhibitors in early neurodevelopment could be a potential cause of autism and there have been calls to factor this into food safety and risk assessments [ 256 , 257 ].…”

Section: Manipulation Of Dna Topology: Dsbs As Genomic Sculptorsmentioning

confidence: 99%

Physiological Roles of DNA Double-Strand Breaks

Khan

Ali

2017

Journal of Nucleic Acids

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Genomic integrity is constantly threatened by sources of DNA damage, internal and external alike. Among the most cytotoxic lesions is the DNA double-strand break (DSB) which arises from the cleavage of both strands of the double helix. Cells boast a considerable set of defences to both prevent and repair these breaks and drugs which derail these processes represent an important category of anticancer therapeutics. And yet, bizarrely, cells deploy this very machinery for the intentional and calculated disruption of genomic integrity, harnessing potentially destructive DSBs in delicate genetic transactions. Under tight spatiotemporal regulation, DSBs serve as a tool for genetic modification, widely used across cellular biology to generate diverse functionalities, ranging from the fundamental upkeep of DNA replication, transcription, and the chromatin landscape to the diversification of immunity and the germline. Growing evidence points to a role of aberrant DSB physiology in human disease and an understanding of these processes may both inform the design of new therapeutic strategies and reduce off-target effects of existing drugs. Here, we review the wide-ranging roles of physiological DSBs and the emerging network of their multilateral regulation to consider how the cell is able to harness DNA breaks as a critical biochemical tool.

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A possible link between nutritional uptake of ubiquitous topoisomerase inhibitors and autism?

Cited by 4 publications

References 18 publications

SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage

SUMO-Targeted DNA Translocase Rrp2 Protects the Genome from Top2-Induced DNA Damage

Top2a promotes the development of social behavior via PRC2 and H3K27me3

Physiological Roles of DNA Double-Strand Breaks

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