Proteomics

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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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Action DRS
341505_Cristina_9plex_F1_L06541.mzid Mzid
341507_Cristina_9plex_F2_L06542.mzid Mzid
341509_Cristina_9plex_F3_L06543.mzid Mzid
341511_Cristina_9plex_F4_L06544.mzid Mzid
341513_Cristina_9plex_F5_L06545.mzid Mzid
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Publications

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]

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