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ACS Central Sci., Oct 23 2024, 10 (10) | https://doi.org/10.1021/acscentsci.4c00967 Loss of Diphthamide Increases DNA Replication Stress in Mammalian Cells by Modulating the Translation of RRM1

Jiaqi Zhao¹, Byunghyun Ahn ^1,2, Hening Lin^1,2,3

¹Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

²Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, United States.

³Howard Hughes Medical Institute, Cornell University, Ithaca, New York 14853, United States.

J.Z. and B.A. contributed equally to this work.

Corresponding Author : Hening Lin

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.

논문정보

형식Research article
게재일2024년 10월 (BRIC 등록일 2024-11-03)
연구진국외 연구진
분야 생명과학 > 분자생물학

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