# Regulation of mRNA processing: Mechanisms and Consequences

> **NIH NIH R35** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2022 · $794,318

## Abstract

Synthesis of eukaryotic mRNAs is a complex process, and includes splicing and 3’ end formation of mRNA
precursors. My lab has studied these processes for many years, including recently how they function in
differentiation and disease. This proposal continues our studies on these topics, and can be divided into the
following areas. mRNA processing in cancer. Work investigating how mutations in genes encoding splicing
factors lead to MDS and other neoplasms will be continued, with an emphasis on SF3B1. Studies to elucidate
both the mechanism(s) by which SF3B1 mutations affect splicing as well as the pathways that are
dysregulated and lead to disease will be pursued. With respect to mechanism, an immediate goal will be to
continue characterizing the SF3B1-interacting region of SUGP1. Another goal is to identify the SUGP1-
interacting RNA helicase and determine its function in normal BP recognition, which will then allow
determination of the detailed mechanism by which SF3B1 mutations disrupt splicing. With respect to pathways,
experiments to elucidate the details of the recently described MAP3K7/p38/GATA1 pathway that underlies
anemia in MDS will be performed. Missplicing events that affect other relevant pathways, such as aberrant
activation of NF-kB, will be studied. FUS and other RBPs in ALS/FTD. With respect to FUS, experiments to
analyze FUS nucleocytoplasmic homeostasis, a process important for formation of toxic cytoplasmic FUS
aggregates, will be continued. Evidence supporting a gating mechanism involving the NPC and interactions
with specific nucleoporins, themselves implicated in amyotrophic lateral sclerosis (ALS), will be pursued. Suggestions that this process may
involve cell-type specificity, with MNs perhaps being more permissive, will be investigated. Experiments
pursing the observation that RBP aggregates and consequent missplicing occur in a large fraction of sporadic
ALS/FTD patient brains in the absence of known mutations will be continued. Aggregates will be isolated from
motor cortex samples and protein/RNA composition determined to investigate what might nucleate their
formation. Regulation of PA factor activity by AS. Experiments investigating the functions of isoforms of the
polyadenylation (PA) factor WDR33 will be pursued. Two short isoforms, v2 and v3, are produced by intronic
PA), and v2 but not v3 is an inner nuclear membrane protein not directly involved in PA. Interacting proteins of
both will be identified, and results suggesting they are upregulated by an NF-kB pathway will be pursued.
Evidence that the two isoforms function in the antiviral response, including to SARS-CoV-2 infection, will be
further investigated. The finding that 45 isoforms of the PA factor Fip1 are produced in humans will be
explored. eRNAs as mRNAs. Results suggesting that certain nuclear unstable lncRNAs, including eRNAs, are
stabilized, exported to the cytoplasm and in some case translated, will be pursued. Observations that up to 5%
of eRNAs...

## Key facts

- **NIH application ID:** 10432005
- **Project number:** 5R35GM118136-07
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** James L. Manley
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $794,318
- **Award type:** 5
- **Project period:** 2016-06-08 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432005

## Citation

> US National Institutes of Health, RePORTER application 10432005, Regulation of mRNA processing: Mechanisms and Consequences (5R35GM118136-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10432005. Licensed CC0.

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