The RNA Transcript, July 5, 2021
Networking, networking, networking!

We're pleased to invite you to connect with us on LinkedIn!
Build and engage with your professional #RNA network, access knowledge, insights and opportunities. Want to join a community of over 155 RNA faculty at a leading research university?

Curious about our first post on LinkedIn? We're hiring assistant professors (tenure track) in RNA science!
Dr. Amanda Garner, Department of Medicinal Chemistry and former member of our Executive Committee, co-leads a special issue of ACS Medicinal Chemistry Letters: "RNA: Opening New Doors in Medicinal Chemistry, a Special Issue."

Overall, this issue highlights the diversity of science in the broad field of RNA-targeted drug discovery. 

Last Wednesday, June 30, we hosted the RNA Collaborative Seminar Series webinar. Did you miss it? Watch it here.

“Dynamic multivalent interactions drive mammalian RNA regulation”
Sethu Pitchiaya, Ph.D., Urology, Medical School, University of Michigan

Dr. Pitchiaya is the June 2021 RNA Society spotlight member!
"Characterizing cellular RNA-protein interaction networks with chemical probes"
Chase Weidmann, Ph.D., Biological Chemistry, Medical School, University of Michigan

Moderator: Mats Ljungman
Tuesday, July 13, Center for RNA Science, Institute for Basic Sciences and Seoul National University, Korea

Olivia Rissland (UCAMC), Jin-Hong Kim (IBS/SNU)
Wednesday, July 14, RNA Collaborative Seminar Series, hosted by iRNA at Istituto Italiano di Tecnologia (IIT)

August 6–7, 3rd International Webinar on Nucleic Acids & CRISPR
REGISTRATION (Mid Term Date: 15/07/2021-149$; Final Term Date: 26/07/2021-199$)

"Cracking the code of DNA and RNA: New insights into the structure and functions of nucleic acids"
This event is a broad audience gathering for exploring the advancement in DNA, RNA, epigenetics, and innovative techniques at molecular and chemical levels.
September 9–10, Rust Belt RNA Meeting 2021, Columbus, Ohio
REGISTRATION IS OPEN, early birds discount until July 23rd.

Keynote speaker: Professor Hashim Al-Hashimi, Duke University School of Medicine 

We are pleased to be a sponsor of this event.
 
For press releases and blog articles about your upcoming top journal publications,
contact Elisabeth Paymal.

Our members' publications are available through Altmetric. Five queries are currently available: "RNA," "microRNA," "Transcriptome," "Translation," and "Molecule." Please make sure to have at least one of these key words in your title or abstract. Below are recent highlights.
RNA: Opening New Doors in Medicinal Chemistry, a Special Issue, Amanda L. Garner and Stevan W. Djuric, ACS Med. Chem. Lett. 2021, 12, 6, 851–853 Publication Date:June 10, 2021, https://doi.org/10.1021/acsmedchemlett.1c00279

Previously considered “difficult to drug” on a structural and selectivity basis, considerable efforts in academia and industry are now being focused on targeting RNA as a therapeutic modality. These efforts are driven based on both the biological significance of RNAs, as well as a growing number of studies implicating aberrant RNA biology in many human diseases.

While biologic approaches continue to play an impactful and ever-growing role in RNA-targeted drug discovery, considerable efforts are now being devoted toward the targeting of RNAs with small molecules. In the issue, both a diversity of RNA types, as well as strategies for small molecule discovery, are highlighted. 
Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain. Shukla, S., Ying, W., Gray, F. et al. Nat Chem Biol 17, 784–793 (2021). https://doi.org/10.1038/s41589-021-00815-5

Abstract: Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B–BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B–BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology.
Sleep loss drives brain region- and cell type-specific alterations in ribosome-associated transcripts involved in synaptic plasticity and cellular timekeeping
Carlos Puentes-Mestril, James Delorme, Lijing Wang, Marcus Donnelly, Donald Popke, Sha Jiang and Sara J. Aton, Journal of Neuroscience, 17 May 2021, JN-RM-1883-20; DOI: https://doi.org/10.1523/JNEUROSCI.1883-20.2021

Significance Statement: Sleep loss-driven changes in transcript and protein abundance have been used as a means to better understand the function of sleep for the brain. Here we use translating ribosome affinity purification (TRAP) to characterize changes in abundance of ribosome-associated transcripts in excitatory and inhibitory neurons in mouse hippocampus and neocortex after a brief period of sleep or sleep loss. We show that these changes are not uniform, but are generally more pronounced in excitatory neurons than inhibitory neurons, and more pronounced in neocortex than in hippocampus.
ELOF1 is a transcription-coupled DNA repair factor that promotes DNA damage-induced RNAPII ubiquitylation, Yana van der Weegen, Klaas de Lint, Diana van den Heuvel, Yuka Nakazawa, Ishwarya V. Narayanan, Noud Klaassen, Annelotte P. Wondergem, Marta San Martin Alonso, Shivani Rampersad, Yuichiro Hara, Kana Kato, Mayuko Shimada, Sylvie M. Noordermeer, Mats Ljungman, Tomoo Ogi, Rob M.F. Wolthuis, and Martijn S. Luijsterburg, Nature Cell Biology, 23:595-607, 2021, https://www.biorxiv.org/content/10.1101/2021.02.25.432427v1

Summary: Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. The binding of the TCR-specific repair factor CSB triggers DNA damage-induced ubiquitylation of RNA polymerase II (RNAPII) at a single lysine (K1268) by the CRL4CSA ubiquitin ligase. However, how the CRL4CSA ligase is specifically directed toward the K1268 site is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to the K1268 site, revealing ELOF1 as a specificity factor that positions CRL4CSA for optimal RNAPII ubiquitylation. Furthermore, drug-genetic interaction screening reveals an unanticipated compensatory TCR pathway in which ELOF1 together with known factors DOT1L and HIRA protect CSB-deficient cells from collisions between transcription and replication machineries. Our study provides a genetic framework of the transcription stress response and reveals key insights into the molecular mechanism of TCR.
Visiting Assistant Professor in Biochemistry at Kalamazoo College
The Department of Chemistry and Biochemistry at Kalamazoo College invites applications for a one-year appointment as a Visiting Assistant Professor with a focus on Biochemistry. Start date, September 2021.
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