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dc.contributor.authorYan, Qingqing
dc.contributor.authorWulfridge, Phillip
dc.contributor.authorDoherty, John
dc.contributor.authorFernández Luna, Juan Manuel 
dc.contributor.authorReal Luna, Pedro José 
dc.contributor.authorTang, Hsin-Yao
dc.contributor.authorSarma, Kavitha
dc.date.accessioned2024-10-02T11:56:49Z
dc.date.available2024-10-02T11:56:49Z
dc.date.issued2022-01-10
dc.identifier.citationYan, S. et. al. Nat Commun 13, 53 (2022). [https://doi.org/10.1038/s41467-021-27722-6]es_ES
dc.identifier.urihttps://hdl.handle.net/10481/95441
dc.description.abstractR-loops are three-stranded nucleic acid structures that accumulate on chromatin in neurological diseases and cancers and contribute to genome instability. Using a proximitydependent labeling system, we identified distinct classes of proteins that regulate R-loops in vivo through different mechanisms. We show that ATRX suppresses R-loops by interacting with RNAs and preventing R-loop formation. Our proteomics screen also discovered an unexpected enrichment for proteins containing zinc fingers and homeodomains. One of the most consistently enriched proteins was activity-dependent neuroprotective protein (ADNP), which is frequently mutated in ASD and causal in ADNP syndrome. We find that ADNP resolves R-loops in vitro and that it is necessary to suppress R-loops in vivo at its genomic targets. Furthermore, deletion of the ADNP homeodomain severely diminishes R-loop resolution activity in vitro, results in R-loop accumulation at ADNP targets, and compromises neuronal differentiation. Notably, patient-derived human induced pluripotent stem cells that contain an ADNP syndrome-causing mutation exhibit R-loop and CTCF accumulation at ADNP targets. Our findings point to a specific role for ADNP-mediated R-loop resolution in physiological and pathological neuronal function and, more broadly, to a role for zinc finger and homeodomain proteins in R-loop regulation, with important implications for developmental disorders and cancers.es_ES
dc.description.sponsorshipNIH (T32CA009171)es_ES
dc.description.sponsorshipGrant from Simons Foundation Autism Research Initiative (670739, K.S.)es_ES
dc.description.sponsorshipNIH New Innovator Award DP2-NS105576 (to K.S.), R50 CA221838 (to H.-Y.T.) and P30 CA010815 (to Wistar Institute Proteomics & Metabolomics Facility)es_ES
dc.language.isoenges_ES
dc.publisherSpringer Naturees_ES
dc.rightsAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleProximity labeling identifies a repertoire of sitespecific R-loop modulatorses_ES
dc.typejournal articlees_ES
dc.rights.accessRightsopen accesses_ES
dc.identifier.doi10.1038/s41467-021-27722-6
dc.type.hasVersionVoRes_ES


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Atribución 4.0 Internacional
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