PXD026473-1

PXD026473 is an original dataset announced via ProteomeXchange.

Title	Proximity labeling identifies a repertoire of site-specific R-loop modulators
Description	R-loops are three stranded nucleic acid structures that accumulate on chromatin in neurological diseases and cancers and that contribute to genome instability. Using a proximity-dependent 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 at R-loops. One of the most consistently enriched proteins at R-loops was activity-dependent neuroprotective protein (ADNP), which is frequently mutated in ASD and causal in ADNP syndrome. We find that ADNP is necessary to suppress R-loops in vivo at its genomic targets and that it resolves R-loops in vitro. Furthermore, deletion of the 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 previously unappreciated role for zinc finger and homeodomain proteins in R-loop regulation, with important implications for developmental disorders and cancers.
HostingRepository	MassIVE
AnnounceDate	2021-11-15
AnnouncementXML	Submission_2021-11-15_11:53:45.427.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hsin-Yao Tang
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Oxidation; Carbamidomethyl
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-03 14:01:59	ID requested
⏵ 1	2021-11-15 11:53:45	announced

no publication

submitter keyword: R-loops , proximity-dependent labeling system, ADNP

Kavitha Sarma
contact affiliation	The Wistar Institute
contact email	ksarma@Wistar.org
lab head
Hsin-Yao Tang
contact affiliation	The Wistar Institute
contact email	tangh@wistar.org
dataset submitter

MassIVE dataset URI

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