Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21

Dae Seok Kim, Cristel V. Camacho, Anusha Nagari, Venkat S. Malladi, Sridevi Challa, W. Lee Kraus

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternative pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduces DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.

Original languageEnglish (US)
Pages (from-to)1270-1285.e14
JournalMolecular cell
Volume75
Issue number6
DOIs
StatePublished - Sep 19 2019

Keywords

  • ADP-ribosylation
  • DDX21
  • PARP inhibitor
  • PARP-1
  • breast cancer
  • poly(ADP-ribose) polymerase-1
  • rDNA transcription
  • ribosome biogenesis
  • small nucleolar RNAs
  • snoRNAs

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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