Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis)

Banerji,Julian

doi:10.3892/ijmm.2015.2285

Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis)

Authors:
- Julian Banerji
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Affiliations: Center for Computational and Integrative Biology, MGH, Simches Research Center, Boston, MA 02114, USA
Published online on: July 15, 2015 https://doi.org/10.3892/ijmm.2015.2285
Pages: 607-626
Copyright: © Banerji . This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The present treatment of childhood T-cell leukemias involves the systemic administration of prokaryotic L-asparaginase (ASNase), which depletes plasma Asparagine (Asn) and inhibits protein synthesis. The mechanism of therapeutic action of ASNase is poorly understood, as are the etiologies of the side-effects incurred by treatment. Protein expression from genes bearing Asn homopolymeric coding regions (N-hCR) may be particularly susceptible to Asn level fluctuation. In mammals, N-hCR are rare, short and conserved. In humans, misfunctions of genes encoding N-hCR are associated with a cluster of disorders that mimic ASNase therapy side-effects which include impaired glycemic control, dislipidemia, pancreatitis, compromised vascular integrity, and neurological dysfunction. This paper proposes that dysregulation of Asn homeostasis, potentially even by ASNase produced by the microbiome, may contribute to several clinically important syndromes by altering expression of N-hCR bearing genes. By altering amino acid abundance and modulating ribosome translocation rates at codon repeats, the microbiomic environment may contribute to genome decoding and to shaping the proteome. We suggest that impaired translation at poly Asn codons elevates diabetes risk and severity.

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