Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders

Stoll, Georg; Pietiläinen, Olli; Linder, Bastian; Suvisaari, Jaana; Brosi, Cornelia; Hennah, William; Leppä, Virpi; Torniainen, Minna; Ripatti, Samuli; Ala‐Mello, Sirpa; Plöttner, Oliver; Rehnström, Karola; Tuulio‐Henriksson, Annamari; Varilo, Teppo; Tallila, Jonna; Kristiansson, Kati; Isohanni, Matti; Kaprio, Jaakko; Eriksson, Johan G.; Raitakari, Olli T.; Lehtimäki, Terho; Järvelin, Marjo‐Riitta; Salomaa, Veikko; Hurles, Matthew E.; Stefánsson, Kári; Peltonen, Leena; Sullivan, Patrick F.; Paunio, Tiina; Lönnqvist, Jouko; Daly, Mark J.; Fischer, Utz; Freimer, Nelson B.; Palotie, Aarno

doi:10.1038/nn.3484

Cited by 154 publications

(267 citation statements)

References 60 publications

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“…In closing, it is relevant to note that in type IA topoisomerases, the Top3 enzymes also form 5Ј-tyrosyl catalytic intermediates (2,42). Thus, further studies are warranted to determine the potential relevance of TDP2 for the repair of Top3␣⅐DNA and Top3␤⅐DNA or RNA complexes (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

Gao

Schellenberg

Huang

et al. 2014

Journal of Biological Chemistry

109

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Background: TDP2 is critical for repairing Top2 cleavage complexes (Top2cc) and as the VPg unlinkase for picornavirus replication. Results: Top2 proteolysis or denaturation is required for TDP2 activity. TDP2 also hydrolyzes Top2cc at ribonucleotides. Conclusion: TDP2 efficiently disjoints relatively large Top2 polypeptide-DNA and -RNA complexes. Significance: Top2 processing is critical prior to its unlinking from DNA or RNA by TDP2.

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Section: Discussionmentioning

confidence: 99%

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

Gao

Schellenberg

Huang

et al. 2014

Journal of Biological Chemistry

109

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“…founder populations are likely to show increased frequencies for many deleterious alleles-another feature that will enhance their utility for mapping these traits (10,11). We previously described, in these pedigrees, multiple heritable and BP-associated phenotypes from the domains of temperament, neurocognition, and neuroanatomy (10).…”

Section: Significancementioning

confidence: 99%

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder

Pagani

Clair

Teshiba

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes. bipolar disorder | endophenotypes | circadian rhythms | actigraphy | behavior Q uantitative sleep and activity measures are hypothesized to be endophenotypes for bipolar disorder (BP). Disturbance of sleep and circadian activity typically precedes and may precipitate the initial onset of BP (1, 2). Decreased sleep and increased activity occur before and during manic and hypomanic episodes. Conversely, increased sleep and decreased activity characterize BP-depression. Extreme diurnal variation in mood features prominently in both mania and depression, whereas shifts in circadian phase (the time within the daily activity cycle at which periodic phenomena such as bed time or awakening occur) can induce mania and ameliorate symptoms of BP-depression (3).Twin studies have identified multiple heritable sleep and activity phenotypes, including sleep duration, sleep quality, phase of activity preference and sleep pattern, and sleep architecture variables [e.g., the amount of slow wave and rapid eye movement (REM) sleep (4) and polysomnography profiles during non-REM sleep (5)]. Euthymic BP individuals, compared with healthy controls, display trait-like alterations in several such phenotypesfor example, sleep time and time in bed, sleep onset latency, and periods of being awake after sleep onset (6). However, no prior investigations have assayed the heritability of such phenotypes in BP individuals and their relatives.We report here the delineation of sleep and activity BP endophenotypes through investigations of 26 pedigrees (n = 558) ascertained for severe BP (BP-I), from the genetically related populations of the Central Valley of Costa Rica (CR) and Antioquia, Colombia (CO) (7-9). Pedigrees ascertained for multiple cases of severe BP (BP-I) should be enriched for extreme values of quantitative traits that are BP endophenotypes, enhancing their utility for genetic mapping studies of such phenotypes. Additionally, su...

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“…These marks, now being referred to as 'RNA epigenetics', can impact RNA secondary and tertiary structure formation, additional post-transcriptional processing, transport, metabolism and functional interactions. Conspicuously, RNA methyltransferase, demethylase and topoisomerase enzymes seem to have emerging roles in stem cell fate determination, neural developmental, synapse formation, neural network activity and cognitive and behavioural functions [94][95][96][97][98][99][100].…”

Section: Discussionmentioning

confidence: 99%

An evolving view of epigenetic complexity in the brain

Qureshi

Mehler

2014

Phil. Trans. R. Soc. B

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Recent scientific advances have revolutionized our understanding of classical epigenetic mechanisms and the broader landscape of molecular interactions and cellular functions that are inextricably linked to these processes. Our current view of epigenetics includes an increasing appreciation for the dynamic nature of DNA methylation, active mechanisms for DNA demethylation, differential functions of 5-methylcytosine and its oxidized derivatives, the intricate regulatory logic of histone post-translational modifications, the incorporation of histone variants into chromatin, nucleosome occupancy and dynamics, and direct links between cellular signalling pathways and the actions of chromatin 'reader', 'writer' and 'eraser' molecules. We also have an increasing awareness of the seemingly ubiquitous roles played by diverse classes of selectively expressed non-coding RNAs in transcriptional, post-transcriptional, post-translational and local and higher order chromatin modulatory processes. These perspectives are still evolving with novel insights continuing to emerge rapidly (e.g. those related to epigenetic regulation of mobile genetic elements, epigenetic mechanisms in mitochondria, roles in nuclear architecture and 'RNA epigenetics'). The precise functions of these epigenetic factors/phenomena are largely unknown. However, it is unequivocal that they serve as key mediators of brain complexity and flexibility, including neural development and aging, cellular differentiation, homeostasis, stress responses, and synaptic and neural network connectivity and plasticity.

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Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders

Cited by 154 publications

References 60 publications

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder

An evolving view of epigenetic complexity in the brain

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