Dataset Information

RNA helicase DDX21 mediates nucleotide stress responses

ABSTRACT: The stress of nucleotide pool reduction regulates transcription in neural crest and melanoma cells. To better understand the molecular response caused by nucleotide stress, we designed a chemical suppressor screen for leflunomide, an inhibitor of dihydroorate dehydrogenase. We found that alterations in the progesterone receptor (Pgr) activity suppressed the neural crest effects of leflunomide. To clarify the mechanism of action, we found that the RNA helicase protein, Ddx21, binds to Pgr, and loss of function of Ddx21 conferred resistance to nucleotide stress in zebrafish embryos. At the molecular level, nucleotide stress reduces DDX21 chromatin occupancy and thus, target gene expression. Together our results show that DDX21 is a transcriptional sensor and mediator of the nucleotide stress response.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Skin

DISEASE(S): Skin Cancer

SUBMITTER: Marian Kalocsay

LAB HEAD: Leonard Zon

PROVIDER: PXD014433 | Pride | 2020-02-06

REPOSITORIES: Pride

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Publications

RNA helicase DDX21 mediates nucleotide stress responses in neural crest and melanoma cells.

Santoriello Cristina C Sporrij Audrey A Yang Song S Flynn Ryan A RA Henriques Telmo T Dorjsuren Bilguujin B Custo Greig Eugenia E McCall Wyatt W Stanhope Meredith E ME Fazio Maurizio M Superdock Michael M Lichtig Asher A Adatto Isaac I Abraham Brian J BJ Kalocsay Marian M Jurynec Michael M Zhou Yi Y Adelman Karen K Calo Eliezer E Zon Leonard I LI

Nature cell biology 20200330 4

The availability of nucleotides has a direct impact on transcription. The inhibition of dihydroorotate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates the effective transcription elongation of genes required for neural crest development and melanoma growth in vivo<sup>1</sup>. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surpri ...[more]

PMID: 32231306

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Project description:Amyloid light chain amyloidosis (AL) is an incurable protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains accumulate as amyloid fibrils in vital organs and cause multi-organ dysfunction that can be rapidly fatal. Current treatment regimens, which include proteasome inhibitors, were developed for the treatment of the more common plasma cell disease multiple myeloma and have demonstrated efficacy in AL amyloidosis. However, use of these agents is frequently limited due to multi-organ dysfunction at presentation, resulting in a median survival of 2-3 years and underscoring the need for novel therapies. By analyzing bone marrow-derived plasma cells from 44 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins that can potentially be targeted by recently-developed BH3 mimetics. In particular, we find that clonal plasma cells are highly dependent on the pro-survival MCL-1 and undergo apoptosis in response to single-agent treatment with an MCL-1 inhibitor. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, which is currently the standard of care for this disease, via the stabilization of Noxa and its direct inhibitory binding to MCL-1. BCL-2 inhibition with the FDA-approved inhibitor venetoclax (ABT-199) sensitizes plasma cells to bortezomib treatment and other front-line therapies, which can be observed in vitro and in vivo. Mass spectrometry-based proteomic analysis reveals changes in signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapy. Overall, our results indicate that BH3 mimetics may be highly effective therapies for AL amyloidosis that exploit inherent and induced dependencies on pro-survival proteins.

Dataset Information

RNA helicase DDX21 mediates nucleotide stress responses

Publications

RNA helicase DDX21 mediates nucleotide stress responses in neural crest and melanoma cells.

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