Cancer Cells Rewire the Genetic Code to Overcome Amino Acid Depletion

Profiling the working of a tumor cell in comparison to a healthy cell provides a mechanistic view of their response to the host immune system. In a new study from the Netherlands Cancer Institute, Amsterdam and Rotterdam University, researchers demonstrate that tumor cells can swap amino acids during protein translation if there is a shortage.

The central dogma of molecular biology is that the genetic code is faithfully transcribed and translated into a functional protein because cells have unique ribosomal components called t-RNA which read the codons on the mRNA to incorporate the corresponding amino acids to build a protein chain. When the immune system detects a tumor cell in the vicinity, the T cells mount an attack by releasing interferon-γ. Authors of this report show that interferon-γ causes a shortage of one particular amino acid, tryptophan in tumor cells which evade the problem by replacing it with another similar-structured amino acid, phenylalanine, suggesting that tumor cells have a codon reassignment strategy to overcome amino acid depletion. 

Proteome-wide and Cancer-specific 

The study, led by Dr. Reuven Agami, head of the Division of Oncogenomics at the Netherlands Cancer Institute, identified that WARS1, tryptophanyl t-RNA synthetase could add phenylalanine(F) to the peptide chain in the event of tryptophan (W) unavailability. This phenomenon is unique to cancerous cells since no W>F substitution was observed in normal tissues. Analysis of cancer proteomes showed an enrichment of W>F clusters. 

This reassignment could provide both advantages and disadvantages to the tumor cells. While the substitution allows for protein synthesis to proceed despite amino acid shortages, it could result in proteins with altered 3D conformation, active sites and substrate specificity for enzymatic activity. It also triggers an immune response by antigen-presentation of modified proteins. This can be exploited to dial up the immune response in the tumor microenvironment. 

Mutations cause fixed changes in protein structure and function. However, amino acid substitutions are induced due to the cell’s adjustment to cellular restrictions during mRNA translation which cause broad range changes to the proteome. 

The authors provide yet another example of conditional reassignment in the genetic code which has been previously observed in mitochondrial proteins, microbes in stressful conditions, and mammals responding to viral infections. The substitution occurs across a range of tumors which could help develop generic anti-tumor therapeutics. Further work on disease-specific substitutions could unravel other less understood rules of the genetic code. 

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Sahana Shankar