# Viral Noncoding RNAs and Cell Transformation

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $672,801

## Abstract

Project Summary/Abstract
The roles of noncoding (nc)RNAs in lymphoid cells harboring each of three oncogenic herpesviruses are being
investigated. Epstein-Barr virus (EBV) infects and transforms human B cells; it is the causative agent of
infectious mononucleosis and is associated with several human cancers. Herpesvirus saimiri (HVS) induces
fatal lymphomas and leukemias in New World monkeys and transforms human T lymphocytes in culture.
Kaposi's sarcoma-associated herpesvirus (KSHV) afflicts immunocompromised individuals and persists in a
latent form until lytic activation. In recent years, we have focused our efforts on the structure and functions of
the two EBV-encoded EBERs, the seven HVS-encoded HSURs and six HVS microRNAs, as well as the KSHV
PAN RNA. These viral ncRNAs are all abundant, conserved between related viruses and bind host proteins to
form ncRNPs. Our functional studies have uncovered novel mechanisms of microRNA biogenesis and decay,
revealed that viral ncRNPs can be essential for nuclear processes as diverse as viral DNA replication (EBER2)
or mRNA export to the cytoplasm (PAN), identified the role of triple helices in RNA stabilization, and
contributed important insights into viral evolution. Most compelling is that our studies of viral ncRNAs have
uncovered the existence of and begun to elucidate novel cellular mechanisms such as the regulation of cellular
microRNA populations and how the polyA tail and 3′UTR may collaborate to stabilize cellular mRNAs.
 Proposed aims will exploit these advances to further investigate the underlying molecular mechanisms. We
shall extend our original discovery of target-directed microRNA decay (TDMD) to identify proteins and
additional RNA signals contributing to cellular microRNA degradation, as well as investigate the role of a
putative small RNA derived from the SARS-CoV-2 genome in regulating host immune responses, with potential
diagnostic/therapeutic implications. We shall establish how its polyA tail as well as internal sequences
contribute to PAN RNA's ability to enable the nuclear export of late lytic mRNAs, leading to virion protein
production and virion release. We shall search cellular transcriptome databases for the presence of RNA
sequence/structure motifs contributing to polyA-3′UTR interactions (and presumably RNA stabilization), as
recently revealed by our high-resolution X-ray analyses. Newly discovered triplex-forming elements (ENEs) in
coronavirus RNAs will be analyzed for their stabilization activity and possible contributions to viral protein
synthesis, with potential therapeutic applications. Extensive interactions between viral transcripts in EBV-
infected cells discovered by psoralen crosslinking will be validated and further analyzed.

## Key facts

- **NIH application ID:** 10553131
- **Project number:** 5R01CA259386-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JOAN A. STEITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $672,801
- **Award type:** 5
- **Project period:** 2022-01-20 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10553131

## Citation

> US National Institutes of Health, RePORTER application 10553131, Viral Noncoding RNAs and Cell Transformation (5R01CA259386-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10553131. Licensed CC0.

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