bims-micpro 2023-11-12 papers

Nat Struct Mol Biol. 2023 Nov 06.

CRISPR-Cas9-based functional interrogation of unconventional translatome reveals human cancer dependency on cryptic non-canonical open reading frames.

Emerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data. Many such ORFs are upregulated in CRC compared to normal tissues and are associated with clinically relevant molecular subtypes. We confirm the in vivo tumor-promoting function of the microprotein SMIMP, encoded by a primate-specific, long noncoding RNA, the expression of which is associated with poor prognosis in CRC, is low in normal tissues and is specifically elevated in CRC and several other cancer types. Mechanistically, SMIMP interacts with the ATPase-forming domains of SMC1A, the core subunit of the cohesin complex, and facilitates SMC1A binding to cis-regulatory elements to promote epigenetic repression of the tumor-suppressive cell cycle regulators encoded by CDKN1A and CDKN2B. Thus, our study reveals a cryptic microprotein as an important component of cohesin-mediated gene regulation and suggests that the 'dark' proteome, encoded by cryptic non-canonical ORFs, may contain potential therapeutic or diagnostic targets.

DOI: https://doi.org/10.1038/s41594-023-01117-1

Trends Biochem Sci. 2023 Nov 01. pii: S0968-0004(23)00276-1. [Epub ahead of print]

Helicases clear hurdles during plant defense protein translation.

Liyuan You, Cuilan Shi, Daowen Wang, Zheng Qing Fu.

Plants undergo translational reprogramming when they are under attack by pathogens. Xiang et al. recently revealed that plant helicases induced by pathogen recognition unwind RNA hairpins upstream of the main open reading frames (mORFs), thus allowing ribosomes to bypass the upstream ORFs (uORFs) and translate downstream defense proteins, a mechanism that is also found in mammals.

Keywords: hairpin; helicase; pathogen; ribosome; start codon; translational reprogramming

DOI: https://doi.org/10.1016/j.tibs.2023.10.007

MicroPubl Biol. 2023 ;2023

Unannotated Open Reading Frame in Saccharomyces cerevisiae Encodes Protein Localizing to the Endoplasmic Reticulum.

Scott Chang, Matthew Joyson, Anna Kelly, Lucas Tang, John Iannotta, April Rich, Nelson Castilho Coelho, Anne-Ruxandra Carvunis.

There are thousands of unannotated translated open reading frames (ORFs) in the Saccharomyces cerevisiae genome. Previous investigation into one such unannotated ORF, which was systemically labeled YGR016C-A based on its genomic coordinates, showed that replacing the ORF's ATG start codon with AAG led to a change in cellular fitness under different stress conditions (Wacholder et al., 2023). This suggested translation of YGR016C-A plays a role in cellular fitness. Here, we investigate Ygr016c-a's subcellular localization to gain insight into its cellular function. Computational prediction tools, co-expression analysis and fluorescence microscopy suggest that the Ygr016c-a protein localizes to the endoplasmic reticulum.

DOI: https://doi.org/10.17912/micropub.biology.000992

Comput Struct Biotechnol J. 2023 ;21 5201-5211

Large-scale ORF screening based on LC-MS to discover novel lncRNA-encoded peptides responding to ionizing radiation and microgravity.

Wanshi Li, Yongduo Yu, Guangming Zhou, Guang Hu, Bingyan Li, Hong Ma, Wenying Yan, Hailong Pei.

In the human genome, 98% of genes can be transcribed into non-coding RNAs (ncRNAs), among which lncRNAs and their encoded peptides play important roles in regulating various aspects of cellular processes and may serve as crucial factors in modulating the biological effects induced by ionizing radiation and microgravity. Unfortunately, there are few reports in space radiation biology on lncRNA-encoded peptides below 10kD due to limitations in detection techniques. To fill this gap, we integrated a variety of methods based on genomics and peptidomics, and discovered 22 lncRNA-encoded small peptides that are sensitive to space radiation and microgravity, which have never been reported before. We concurrently validated the transmembrane helix, subcellular localization, and biological function of these small peptides using bioinformatics and molecular biology techniques. More importantly, we found that these small peptides function independently of the lncRNAs that encode them. Our findings have uncovered a previously unknown human proteome encoded by 'non-coding' genes in response to space conditions and elucidated their involvement in biological processes, providing valuable strategies for individual protection mechanisms for astronauts who carry out deep space exploration missions in space radiation environments.

Keywords: Long non-coding RNA; Microgravity; Multi-omics integration; Peptide; Space radiation

DOI: https://doi.org/10.1016/j.csbj.2023.10.040