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 journalArticle

5 Citations (Scopus)

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

Fingerprint

Small Nucleolar RNA
RNA Helicases
Ribosomes
Ribosomal DNA
Adenosine Diphosphate
Growth
DNA Repair
Breast Neoplasms
Neoplasms
Protein Biosynthesis
Heterografts
DNA Damage
Poly(ADP-ribose) Polymerase Inhibitors
Mutation

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. / Kim, Dae Seok; Camacho, Cristel V.; Nagari, Anusha; Malladi, Venkat S.; Challa, Sridevi; Kraus, W. Lee.

In: Molecular cell, Vol. 75, No. 6, 19.09.2019, p. 1270-1285.e14.

Research output: Contribution to journalArticle

Kim, Dae Seok ; Camacho, Cristel V. ; Nagari, Anusha ; Malladi, Venkat S. ; Challa, Sridevi ; Kraus, W. Lee. / Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. In: Molecular cell. 2019 ; Vol. 75, No. 6. pp. 1270-1285.e14.
@article{8ea06a7316344a68948ab594d9f16e33,
title = "Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21",
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.",
keywords = "ADP-ribosylation, breast cancer, DDX21, PARP inhibitor, PARP-1, poly(ADP-ribose) polymerase-1, rDNA transcription, ribosome biogenesis, small nucleolar RNAs, snoRNAs",
author = "Kim, {Dae Seok} and Camacho, {Cristel V.} and Anusha Nagari and Malladi, {Venkat S.} and Sridevi Challa and Kraus, {W. Lee}",
year = "2019",
month = "9",
day = "19",
doi = "10.1016/j.molcel.2019.06.020",
language = "English (US)",
volume = "75",
pages = "1270--1285.e14",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21

AU - Kim, Dae Seok

AU - Camacho, Cristel V.

AU - Nagari, Anusha

AU - Malladi, Venkat S.

AU - Challa, Sridevi

AU - Kraus, W. Lee

PY - 2019/9/19

Y1 - 2019/9/19

N2 - 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.

AB - 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.

KW - ADP-ribosylation

KW - breast cancer

KW - DDX21

KW - PARP inhibitor

KW - PARP-1

KW - poly(ADP-ribose) polymerase-1

KW - rDNA transcription

KW - ribosome biogenesis

KW - small nucleolar RNAs

KW - snoRNAs

UR - http://www.scopus.com/inward/record.url?scp=85072154003&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072154003&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2019.06.020

DO - 10.1016/j.molcel.2019.06.020

M3 - Article

C2 - 31351877

AN - SCOPUS:85072154003

VL - 75

SP - 1270-1285.e14

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -