Biology subjects

Kusnadi, E. P.

Publications and source records attributed to Kusnadi, E. P..

4 recordsLinked to original sources

bioRxiv2026

SMAD4 loss drives chromosomal instability during tumourigenesis via translational reprogramming

Chromosomal instability (CIN), arising from errors in chromosome segregation during cell division, is a hallmark of cancer. Whilst CIN can result from several mitotic defects, the mechanisms that initiate CIN to drive tumourigenesis remain incompletely understood. Here, we show that loss of SMAD4 reprograms translation to induce CIN, resulting in tumour formation. Multi-omics analysis of tumourigenesis models driven by loss of SMAD4 complemented by functional studies demonstrate that loss of SMAD4 in pre-neoplastic cells leads to dysfunctional mitosis and an altered global translation landscape. We show that CDK11B is translationally downregulated in SMAD4-\- cells, and re-expression of the mitosis-specific isoform of this protein (CDK11B-p58) rescues the mitotic defects. Analysis of patient tumours reveals a strong correlation between markers of CIN and SMAD4 status, indicating the clinical relevance of this phenotype. Collectively, we reveal a previously unrecognised role for SMAD4 as a gatekeeper for CIN-mediated tumourigenesis via regulation of translation.

cancer biology↗

bioRxiv2026

Di-codon organization links tRNA modifications to cancer cell proteome composition

Hormone-signalling modulates levels of tRNA-modifying enzymes, including ELP3, in cancer cells. Here we show that ELP3 is required to sustain proliferation in prostate cancer cells. Intriguingly, although ELP3 modifies tRNA at the U34-position, the ELP3-sensitive proteome was poorly explained by frequencies of codons requiring U34-modified tRNA for decoding. Instead, we identified six codon pairs (herein denoted ELP3 down di-codons "E3dDCs") that, in concert with local sequence context and 5UTR features affecting translation initiation, explain ELP3-sensitive protein expression. Moreover, despite activation of the canonical integrated stress response upon ELP3 suppression, the associated expression program was paradoxically suppressed in a fashion correlating with higher E3dDC frequencies. E3dDCs were also enriched in mitotic regulators, and ELP3-suppression caused mitotic defects that limited proliferation. Therefore, ELP3 regulates proteome composition via E3dDCs that, depending on their local sequence context and translation initiation activity, determine protein expression and downstream cellular phenotypes upon reduced levels of U34-modified tRNA.

molecular biology↗

bioRxiv2019

Reprogrammed mRNA translation drives metabolic response to therapeutic targeting of ribosome biogenesis

Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA Polymerase I (Pol I) transcription, revealed single agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here we show that this improved efficacy is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this co-treatment is driven by translational re-wiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies identify the molecular mechanisms underpinning the response of blood cancers to selective ribosome biogenesis inhibitors and identify metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.

cancer biology↗

bioRxiv2019

RNA binding kinase UHMK1 regulates therapy induced metabolic adaptation in BRAFV600 melanoma

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by a residual disease that results in relapse. This residual disease is characterized by drug-induced adaptation, that in melanoma includes altered metabolism. Here, we examined how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNAi screen and global gene expression profiling. This systematic approach revealed post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA binding kinase UHMK1 interacts with mRNAs that encode metabolic proteins and selectively controls their transport and translation during adaptation to BRAF targeted therapy. Inactivation of UHMK1 improves metabolic response to BRAF targeted therapy and delays resistance to BRAF and MEK combination therapy in vivo. Our data support a model wherein post-transcriptional gene expression pathways regulate metabolic adaptation underpinning targeted therapy response and suggest inactivation of these pathways may delay disease relapse.

cancer biology↗