Proximity labeling identifies a repertoire of sitespecific R-loop modulators
Metadatos
Afficher la notice complèteAuteur
Yan, Qingqing; Wulfridge, Phillip; Doherty, John; Fernández Luna, Juan Manuel; Real Luna, Pedro José; Tang, Hsin-Yao; Sarma, KavithaEditorial
Springer Nature
Date
2022-01-10Referencia bibliográfica
Yan, S. et. al. Nat Commun 13, 53 (2022). [https://doi.org/10.1038/s41467-021-27722-6]
Patrocinador
NIH (T32CA009171); Grant from Simons Foundation Autism Research Initiative (670739, K.S.); NIH New Innovator Award DP2-NS105576 (to K.S.), R50 CA221838 (to H.-Y.T.) and P30 CA010815 (to Wistar Institute Proteomics & Metabolomics Facility)Résumé
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.