PXD027000-1

PXD027000 is an original dataset announced via ProteomeXchange.

Title	CGG repeat RNA binding protein capture identifies SRSF protein kinase 1 as a modulator of RAN translation and suppressor of repeat toxicity
Description	Transcribed CGG repeat expansions cause the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic peptides in the cytoplasm. To identify proteins involved in these processes, we employed a CGG repeat RNA-tagging system to capture repeat associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine-rich domain) proteins that interact selectively with CGG repeats basally and under cellular stress. These same proteins modify toxicity in a Drosophila model of FXTAS. Genetic or pharmacological targeting of serine/arginine protein kinases (SRPKs) inhibits RAN translation in cells and toxicity in both FXTAS and C9orf72 ALS/FTD model flies. Furthermore, SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. These findings demonstrate roles for CGG repeat RNA binding proteins in repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.
HostingRepository	PRIDE
AnnounceDate	2021-09-28
AnnouncementXML	Submission_2021-09-27_23:01:56.679.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	INDRANIL MALIK
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C labeled residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-29 21:18:24	ID requested
⏵ 1	2021-09-27 23:01:57	announced

Malik I, Tseng YJ, Wright SE, Zheng K, Ramaiyer P, Green KM, Todd PK, SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity. EMBO Mol Med, 13(11):e14163(2021) [pubmed]

submitter keyword: RAN translation, repeat RNA

Peter K. Todd
contact affiliation	Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
contact email	petertod@umich.edu
lab head
INDRANIL MALIK
contact affiliation	UNIVERSITY OF MICHIGAN
contact email	inmalik@umich.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027000
     1. Label: PRIDE project
     2. Name: CGG repeat RNA binding protein capture identifies SRSF protein kinase 1 as a modulator of RAN translation and suppressor of repeat toxicity