Publications by authors named "Anant A Agrawal"

The production of a mature mRNA requires coordination of multiple processing steps, which ultimately control its content, localization, and stability. These steps include some of the largest macromolecular machines in the cell, which were, until recently, considered undruggable due to their biological complexity. Building from an expanded understanding of the underlying mechanisms that drive these processes, a new wave of therapeutics is seeking to target RNA processing.

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Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1.

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Article Synopsis
  • SF3B is a crucial multi-protein complex that helps recognize and select the branch site during the process of pre-mRNA splicing, which is essential for gene expression.
  • The study presents the crystal structure of SF3B when bound to pladienolide B (PB), a splicing modulator known for its ability to inhibit tumor cell growth.
  • PB prevents SF3B from transitioning to its closed form necessary for splicing by wedging open the complex, revealing important interactions that could inform future drug design efforts targeting cancer.
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Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations.

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Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells.

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We identify and characterize novel in-frame deletions in chronic lymphocytic leukemia.These deletions are functionally similar to well-known hotspot mutations and are sensitive to splicing modulation.

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Recently splicing has been recognized as a key pathway in cancer. Although aberrant splicing has been shown to be a consequence of mutations or the abnormal expression of splicing factors (trans-effect changes) or mutations in the splicing sequences (cis-effect mutations), the connections between aberrant splicing and cancer initiation or progression are still not well understood. Here we review the mutational landscape of splicing factors in cancer and associated splicing consequences, along with the most important examples of the therapeutic approaches targeting the spliceosome currently being investigated in oncology.

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Acquired point mutations of pre-mRNA splicing factors recur among cancers, leukemias, and related neoplasms. Several studies have established that somatic mutations of a U2AF1 subunit, which normally recognizes 3' splice site junctions, recur among myelodysplastic syndromes. The U2AF2 splicing factor recognizes polypyrimidine signals that precede most 3' splice sites as a heterodimer with U2AF1.

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How the essential pre-mRNA splicing factor U2AF(65) recognizes the polypyrimidine (Py) signals of the major class of 3' splice sites in human gene transcripts remains incompletely understood. We determined four structures of an extended U2AF(65)-RNA-binding domain bound to Py-tract oligonucleotides at resolutions between 2.0 and 1.

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Article Synopsis
  • Recurrent mutations in the spliceosome, particularly in the SF3B1 component, are linked to several human cancers but their exact roles in cancer progression and treatment are not fully understood.
  • SF3B1 mutations lead to common and tumor-specific splicing defects, primarily causing abnormal selection of the 3' splice sites, which impacts RNA splicing accuracy.
  • Around 50% of mRNAs affected by these splicing errors are targeted for decay, resulting in reduced gene and protein expression, highlighting the functional importance of SF3B1 mutations in cancer.
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Purine interruptions of polypyrimidine (Py) tract splice site signals contribute to human genetic diseases. The essential splicing factor U2AF(65) normally recognizes a Py tract consensus sequence preceding the major class of 3' splice sites. We found that neurofibromatosis- or retinitis pigmentosa-causing mutations in the 5' regions of Py tracts severely reduce U2AF(65) affinity.

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Degenerate splice site sequences mark the intron boundaries of pre-mRNA transcripts in multicellular eukaryotes. The essential pre-mRNA splicing factor U2AF(65) is faced with the paradoxical tasks of accurately targeting polypyrimidine (Py) tracts preceding 3' splice sites while adapting to both cytidine and uridine nucleotides with nearly equivalent frequencies. To understand how U2AF(65) recognizes degenerate Py tracts, we determined six crystal structures of human U2AF(65) bound to cytidine-containing Py tracts.

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