Biology subjects

Truesdell, S. S.

Publications and source records attributed to Truesdell, S. S..

3 recordsLinked to original sources

bioRxiv2023

Regulation of RNA methylation by therapy treatment, promotes tumor survival

Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2 phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2 prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival. One sentence summarym6A enzyme translation upon therapy stress, promotes tumor survival

molecular biology↗

bioRxiv2021

Ribosome changes elicit non-canonical translation for chemosurvival in G0 leukemic cells

Quiescent leukemic cells survive chemotherapy, with translation changes. Our data reveal that FXR1, a protein amplified in several aggressive cancers, increases in quiescent and chemo- treated leukemic cells, and promotes chemosurvival. This suggests undiscovered roles for this RNA- and ribosome-associated protein in chemosurvival. FXR1 depletion decreases translation and ribosome subunits, with altered rRNAs, snoRNAs, and ribosomal proteins (RPs). We find that FXR1 binds factors that promote ribosome gene transcription and bind snoRNAs. Ribosome changes increased in FXR1-overexpressing cells, including increased snoRNAs and RPLP0/uL10, activate eIF2 kinases. Accordingly, phospho-eIF2 increases, enabling non- canonical translation of survival and immune regulators in FXR1-overexpressing cells. Overriding these with inhibitors reduces chemosurvival. Thus, increased FXR1 in quiescent or chemo-treated leukemic cells, alters ribosomes that trigger stress signals to re-direct translation for chemosurvival. One Sentence SummaryFXR1 alters ribosomes in G0, which induce stress signals to elicit noncanonical translation for AML drug and immune survival.

molecular biology↗

bioRxiv2018

A post-transcriptional program of chemoresistance by AU-rich elements/TTP in cancer quiescence

BackgroundQuiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown.\n\nResultsWe induced chemoresistant and quiescent (G0) leukemic cells by serum-starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the up-regulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, tristetraprolin (TTP) in G0. This permits expression of ARE-bearing TNF and DUSP1 that promote chemoresistance. Conversely, inhibition of TTP phophorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNF--prior to or along with chemotherapy--substantially reduced chemoresistance in primary leukemic cells ex vivo and in vivo.\n\nConclusionsThese studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE bearing mRNAs that promote chemoresistance. By disrupting this pathway, we developed an effective combination therapy against chemosurvival.

cancer biology↗