@misc{10481/95441,
year = {2022},
month = {1},
url = {https://hdl.handle.net/10481/95441},
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.},
organization = {NIH (T32CA009171)},
organization = {Grant from Simons Foundation Autism Research Initiative
(670739, K.S.)},
organization = {NIH New Innovator Award DP2-NS105576 (to K.S.), R50 CA221838
(to H.-Y.T.) and P30 CA010815 (to Wistar Institute Proteomics & Metabolomics
Facility)},
publisher = {Springer Nature},
title = {Proximity labeling identifies a repertoire of sitespecific R-loop modulators},
doi = {10.1038/s41467-021-27722-6},
author = {Yan, Qingqing and Wulfridge, Phillip and Doherty, John and Fernández Luna, Juan Manuel and Real Luna, Pedro José and Tang, Hsin-Yao and Sarma, Kavitha},
}