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.

Expression signature of six‐snoRNA serves as novel non‐invasive biomarker for diagnosis and prognosis prediction of renal clear cell carcinoma

“…48,49 Therefore, we inferred that USP34 or SNORA70B might bind WNT pathway-related protein to activate it. 48,49 Therefore, we inferred that USP34 or SNORA70B might bind WNT pathway-related protein to activate it.…”

“…Lasted studies have reported that snoRNAs could directly bind to functional protein to promote tumorigenesis. 48,49 Therefore, we inferred that USP34 or SNORA70B might bind WNT pathway-related protein to activate it.…”

PARP and PARG inhibitors in cancer treatment

“…PARP inhibitors are also effective in Ewing's sarcomas by blocking, on the one hand, PARP1-dependent transcriptional activation effects of ETS gene fusions such as EWS-FLI-1, and by exacerbating DNA damage on the other (Brenner et al 2012). Furthermore, PARP inhibitors reduce rDNA transcription and ribosome biogenesis in BRCA1/2-proficient cancer cells by preventing DDX21 ADP-ribosylation, and thereby reduce breast cancer growth (Kim et al 2019).…”

Small nucleolar RNAs: continuing identification of novel members and increasing diversity of their molecular mechanisms of action

“…ASO-mediated knockdown of SNORA74A engendered a substantial decrease in DDX21 ADPRylation and cell proliferation, confirming that snoRNAs can activate PARP-1 in the absence of DNA damage. It was also shown that DDX21 can bind snoRNAs such as SCARNA2 on its C-terminal RNA-binding domain [74]. These snoRNAs were suggested to compete with the PARP-1 and DDX21 interactions.…”

“…The inhibition of PARP-1 is helpful in the treatment of cancers because it causes accumulation of DNA damage and synthetic lethality of cancer cells presenting defects in homologous recombination (HR)-mediated DNA repair machinery [72]. However, even tumors with non-mutated HR machinery were recently shown to be affected by PARP inhibitors [73], and Kim et al [74] discovered a mechanism that can explain this. Indeed, several mature H/ACA box snoRNAs (notably SNORA73A, SNORA73B and SNORA74A) can bind to PARP-1, leading to the activation of its ADPRylation (PAR) function.…”