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Proximity labeling identifies a repertoire of sitespecific R-loop modulators
dc.contributor.author | Yan, Qingqing | |
dc.contributor.author | Wulfridge, Phillip | |
dc.contributor.author | Doherty, John | |
dc.contributor.author | Fernández Luna, Juan Manuel | |
dc.contributor.author | Real Luna, Pedro José | |
dc.contributor.author | Tang, Hsin-Yao | |
dc.contributor.author | Sarma, Kavitha | |
dc.date.accessioned | 2024-10-02T11:56:49Z | |
dc.date.available | 2024-10-02T11:56:49Z | |
dc.date.issued | 2022-01-10 | |
dc.identifier.citation | Yan, S. et. al. Nat Commun 13, 53 (2022). [https://doi.org/10.1038/s41467-021-27722-6] | es_ES |
dc.identifier.uri | https://hdl.handle.net/10481/95441 | |
dc.description.abstract | R-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.sponsorship | NIH (T32CA009171) | es_ES |
dc.description.sponsorship | Grant from Simons Foundation Autism Research Initiative (670739, K.S.) | es_ES |
dc.description.sponsorship | NIH 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.iso | eng | es_ES |
dc.publisher | Springer Nature | es_ES |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.title | Proximity labeling identifies a repertoire of sitespecific R-loop modulators | es_ES |
dc.type | journal article | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.identifier.doi | 10.1038/s41467-021-27722-6 | |
dc.type.hasVersion | VoR | es_ES |