Loss of m¹acp³Ψ Ribosomal RNA Modification Is a Major Feature of Cancer

Area of Science:

• Molecular Biology
• Oncology
• RNA Biology

Background:

• The ribosome, a crucial RNA-protein complex for translation, has its core formed by ribosomal RNA (rRNA).
• While ribosomal protein gene mutations are known oncogenic drivers, oncogenic rRNA variants have not been identified.
• A unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (m¹acp³Ψ), is conserved at the peptidyl decoding site of rRNA.

Purpose of the Study:

• To identify and characterize cancer-specific rRNA variants.
• To investigate the functional consequences of altered m¹acp³Ψ modification in cancer.
• To explore the potential of m¹acp³Ψ-deficient rRNA as a therapeutic target.

Main Methods:

• Identification of single-nucleotide variations in 18S rRNA in cancer patients.
• Analysis of m¹acp³Ψ modification levels in tumor tissues.
• Creation of an m¹acp³Ψ knockout model.
• Characterization of translational signatures in tumors and knockout models.

Main Results:

• A cancer-specific single-nucleotide variation in 18S rRNA at nucleotide 1248.U was found in up to 45.9% of colorectal carcinoma (CRC) patients and across >22 cancer types.
• A subset of CRC tumors exhibited sub-stoichiometric m¹acp³Ψ modification (hypo-m¹acp³Ψ) compared to normal tissues.
• Both the m¹acp³Ψ knockout model and hypo-m¹acp³Ψ patient tumors displayed a translational signature with highly abundant ribosomal proteins.

Conclusions:

• The identified 18S rRNA variation and associated hypo-m¹acp³Ψ modification define a novel class of "onco-ribosomes".
• These "onco-ribosomes" may play a role in oncogenesis.
• m¹acp³Ψ-deficient rRNA presents a potential novel chemotherapeutic target for cancer treatment.