PXD057390

PXD057390 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial ribosomal RNA is the target of functionally dominant hotspot mutations in cancer
Description	The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,079 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) RNA subunits of the mitochondrial ribosome. Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions participating in Watson-Crick base pairing and tended to arise at positions under strong purifying selection in the germline. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%, which were corroborated with single cell profiling of mtDNA heteroplasmy and gene expression. Mutation of evolutionarily conserved and germline constrained positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a novel class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.
HostingRepository	PRIDE
AnnounceDate	2025-09-11
AnnouncementXML	Submission_2025-09-11_02:08:16.938.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD057390
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Sergio Lilla
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	methionine oxidation with neutral loss of 64 Da; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-31 04:21:56	ID requested
⏵ 1	2025-09-11 02:08:17	announced

10.6019/PXD057390;

submitter keyword: Mitochondrial DNA mutation, Heteroplasmy, Cancer, MT-RNR1, m.1227G>A

Sara Rossana Zanivan
contact affiliation	CRUK Scotland Institute for Cancer Research - Switchback Rd, Bearsden, Glasgow G61 1BD - United Kingdom
contact email	s.zanivan@crukscotlandinstitute.ac.uk
lab head
Sergio Lilla
contact affiliation	Proteomics
contact email	s.lilla@beatson.gla.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057390
     1. Label: PRIDE project
     2. Name: Mitochondrial ribosomal RNA is the target of functionally dominant hotspot mutations in cancer