Jelinek, T. | bioRxiv Science

bioRxiv2024

Mutagenic impact and evolutionary influence of radiotherapy in hematologic malignancies

Ionizing radiotherapy (RT) is a widely used palliative and curative treatment strategy for malignancies. In solid tumors, RT-induced double strand breaks lead to the accumulation of indels, and their repair by non-homologous end-joining has been linked to the ID8 mutational signature in resistant cells. However, the extent of RT-induced DNA damage in hematologic malignancies and its impact on their evolution and interplay with commonly used chemotherapies has not yet been explored. Here, we interrogated 580 whole genome sequencing (WGS) from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet, it was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode we demonstrate that a single RT-resistant cell may seed systemic relapse.

genomics↗

bioRxiv2023

Length-dependent translation efficiency of ER-destined proteins

Gene expression resulting in the generation of new proteins is a fundamental process critical for every living organism. Particularly in eukaryotic cells, complex organization of the cell body requires fine-tuning of every step prior to de novo protein synthesis. To ensure proper localization, certain mRNAs possess unique signal sequence, which destinies the translation apparatus to the specific organelle. Here we focus on the mechanisms governing the translation of signal sequence-bearing mRNAs, which encode proteins targeted to the endoplasmic reticulum (ER). The binding of a signal-recognition particle (SRP) to the translation machinery halts protein synthesis until the mRNA-ribosome complex reaches ER membrane. The commonly accepted model suggests that mRNA containing the ER signal peptide continuously repeats the cycle of SRP binding followed by association and dissociation with ER. In contrast with the current view, we show that the long mRNAs remain on the ER while being translated. On the other hand, due to a low ribosome occupancy, the short mRNAs continue the cycle always facing the translation pause. Ultimately, this leads to a significant drop in the translation efficiency of small, ER-targeted proteins. The proposed mechanism advances our understanding of selective protein synthesis in eukaryotic cells and provides new avenues to enhance protein production in biotechnological settings.

molecular biology↗