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Ribosome ADP-ribosylation: A mechanism for maintaining protein homeostasis in cancers

Jie Ni1,2, Jiayin Gao3, Qin Li1

  • 1Department of Ultrasound, Taizhou People's Hospital, Taizhou, China.

Cell Biology International
|December 13, 2021
PubMed

Insights

Cancer cells utilize ribosome MARylation to control protein synthesis and prevent toxic aggregation, supporting tumor growth. This process involves NMNAT-2 and PARP-16, offering new therapeutic targets for cancer treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer cells require tight regulation of protein synthesis and proteostasis for survival and proliferation.
  • Toxic protein aggregation can impede cancer cell growth and is a potential vulnerability.
  • Ribosome modifications play a crucial role in cellular homeostasis and disease states.

Purpose of the Study:

  • To investigate the role of ribosome MARylation in maintaining proteostasis within cancer cells.
  • To elucidate the molecular mechanism by which ribosome MARylation impacts protein synthesis and aggregation.
  • To explore the potential of targeting ribosome MARylation for cancer therapy.

Main Methods:

  • Investigated the function of NMNAT-2 (cytosolic NAD+ synthase) and PARP-16 in mediating ribosomal protein MARylation.
  • Analyzed the effect of ribosome MARylation on polysome assembly and function.
  • Examined the impact of altered MARylation on mRNA 3'-untranslated region (3'-UTR) stem-loop structures and protein synthesis.
  • Assessed the consequences of deleting PARP-16 or NMNAT-2 on cancer cell growth and protein aggregation.

Main Results:

  • Ribosome MARylation, mediated by NMNAT-2 and PARP-16, reduces protein synthesis and prevents toxic protein aggregation in cancer cells.
  • MARylation regulates polysome function via mRNA 3'-UTR stem-loop structures, supporting cancer cell growth.
  • Deletion of PARP-16 or NMNAT-2 enhances protein synthesis, promotes aggregation, and inhibits cancer cell proliferation.

Conclusions:

  • Ribosome MARylation is a key mechanism for maintaining proteostasis in cancer.
  • The NMNAT-2/PARP-16 axis is critical for ribosome MARylation and cancer cell survival.
  • Targeting ribosome MARylation presents a novel therapeutic strategy for cancer treatment.
Keywords:
NAD+NMNAT-2PARP-16cancersribosome MARylation

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