PXD047572

PXD047572 is an original dataset announced via ProteomeXchange.

Title	ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans
Description	ARMC5 is an armadillo domain (ARM)-containing protein. We found that Armc5 KO mice had an increased incidence of neural tube defects (NTDs). ARMC5 is the substrate recognition component of a ubiquitin ligase that targets POLR2A, the largest subunit of RNA polymerase II (Pol II). Surprisingly, the absence of ARMC5 caused the accumulation of not only POLR2A, but most of the other 11 Pol II subunits associated with POLR2A, indicating that the degradation of the whole Pol II complex is compromised. This did not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 KO only dysregulated 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical for folate metabolism and vital in neural tube development, was downregulated in the KO intestine, suggesting that it is a downstream effector gene for NTD. To assess whether ARMC5 gene mutation was associated with human NTD, we conducted whole-exome sequencing of 511 patients with myelomeningocele, a severe form of NTD. Nine deleterious single nucleotide variants were discovered in the ARMC5 coding sequence. Four of them were validated in that they weakened the interaction between ARMC5 and POLR2A; consequently, POLR2A ubiquitination was decreased. This proves that our findings in mice are relevant to human NTD; it also supports the role of Pol II in mediating NTD pathogenesis. Our findings indicate that mutations in ARMC5 increase the risk of NTD and support the role of Pol II in NTD pathogenesis. Further investigation is needed to determine the cause-and-effect relationship between an enlarged Pol II pool and NTD and to validate the potential role of downregulated FOLH1 expression in NTD pathogenesis.
HostingRepository	PRIDE
AnnounceDate	2023-12-06
AnnouncementXML	Submission_2023-12-06_08:43:11.738.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD047572
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Christian Poitras
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-06 05:25:02	ID requested
⏵ 1	2023-12-06 08:43:12	announced

10.6019/PXD047572;

submitter keyword: myelomeningocele,ARMC5, Pol II pool size, FOLH1, 12 subunits of Pol II, POLR2A-specific E3, ubiquitin ligase, Cullin 3, neural tube defects

Benoit Coulombe
contact affiliation	Director, Translational Proteomics Research Unit, IRCM Director, Biomarker Pipeline for Precision Medicine Strategic Initiative Full IRCM Research Professor Full Research Professor, Department of Biochemistry and Molecular Medicine (accreditation for the Molecular Biology Programs), Université de Montréal Holder of the Bell-Bombardier Chair of Excellence Person in charge of responsible conduct of research, IRCM
contact email	benoit.coulombe@ircm.qc.ca
lab head
Christian Poitras
contact affiliation	Laboratory of Gene Transcription and Proteomics Discovery Platform, Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada
contact email	christian.poitras@ircm.qc.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047572
     1. Label: PRIDE project
     2. Name: ARMC5 controls the degradation of most Pol II subunits, and ARMC5 mutation increases neural tube defect risks in mice and humans