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 language | English (US) |
|---|---|
| Pages (from-to) | 1270-1285.e14 |
| Journal | Molecular cell |
| Volume | 75 |
| Issue number | 6 |
| DOIs | |
| State | Published - Sep 19 2019 |
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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 journal › Article
}
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 -