Loss of m¹acp³Ψ ribosomal RNA modification is a major feature of cancer

Abstract

<jats:title>Summary</jats:title><jats:p>The ribosome is an RNA-protein complex essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We discovered a cancer-specific single nucleotide variation in 18S rRNA at nucleotide 1248.U in up to 45.9% of colorectal carcinoma (CRC) patients and present across &gt;22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (m<jats:sup>1</jats:sup>acp<jats:sup>3</jats:sup>Ψ), a &gt;1 billion years conserved RNA modification at the ribosome’s peptidyl decoding-site. A sub-set of CRC tumors we term ‘hypo-m<jats:sup>1</jats:sup>acp<jats:sup>3</jats:sup>Ψ’, show sub-stoichiometric m<jats:sup>1</jats:sup>acp<jats:sup>3</jats:sup>Ψ-modification unlike normal control tissues. A m<jats:sup>1</jats:sup>acp<jats:sup>3</jats:sup>Ψ knockout model and hypo-m<jats:sup>1</jats:sup>acp<jats:sup>3</jats:sup>Ψ patient tumors share a translational signature, characterized by highly abundant ribosomal proteins. Thus, m<jats:sup>1</jats:sup>acp<jats:sup>3</jats:sup>Ψ-deficient rRNA forms an uncharacterized class of ‘onco-ribosome’ which may serve as a chemotherapeutic target for treating cancer patients.</jats:p>

CLIP-Seq Analysis Enables the Design of Ribosomal RNA Bait Oligonucleotides That Protect AgainstC9ORF72ALS/FTD-Associated Poly-GR Pathophysiology

“…(Abraham et al, 2015) using Chemistry at Harvard Macromolecular Mechanics (CHARMM) 36 force field for all-atomistic dynamic simulations that represent all the atoms of the system (Best et al, 2012; Brooks et al, 2009; Denning et al, 2011; MacKerell et al, 1998; MacKerell et al, 2000; Vanommeslaeghe et al, 2010). Force field has been widely used for simulation studies of proteins, peptides and nucleic acids (Babaian et al, 2020; Cook et al, 2020; Kognole and MacKerell, 2020; Suomivuori et al, 2020; Zhu et al, 2012). The experimental system was set up with a constant number of molecules, pressure and temperature, in a 100 mM NaCl environment with TIP3P water (Jorgensen et al, 1983).…”