Work

Loss of Diphthamide Increases DNA Replication Stress in Mammalian Cells by Modulating the Translation of RRM1

Year: 2024

Type: article

Abstract: Diphthamide (DPH) is a highly conserved post-translational modification exclusively present in eukaryotic translation elongation factor 2 (eEF2), with its loss leading to embryonic lethality in mice and developmental disorders in humans. In this study, we unveil the role of diphthamide in mammalian cell DNA damage stress, with a particular emphasis on DNA replication stress. We developed a systematic strategy to identify human proteins affected by diphthamide with a combination of computational profiling and quantitative proteomics. Through this approach, we determine that the translation of RRM1 is modulated by diphthamide via -1 frameshifting. Importantly, our results reveal that the dysregulation of RRM1 translation in DPH-deficient cells is causally linked to elevated DNA replication stress. These findings provide a potential explanation for how diphthamide deficiency leads to cancer and developmental defects in humans.

Source: ACS Central Science

DOI: 10.1021/acscentsci.4c00967

Authors: Jiaqi Zhao, Byunghyun Ahn, Hening Lin

Institutions: Cornell University, Howard Hughes Medical Institute

Language: English

Topic: RNA and protein synthesis mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: diamond

Funders: Howard Hughes Medical Institute, National Institutes of Health, National Institute of General Medical Sciences