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

inhibitors 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 growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. binds to snoRNAs, which stimulate Pduanyu37-1 catalytic activity in the nucleolus independent of DNA damage. Activated Pduanyu37-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with 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 Pduanyu37-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of Pduanyu37i in cancer cells lacking defects in DNA repair whose growth is inhibited by

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