Abstract
DHX9 is a DExH-box helicase family member with key regulatory roles in a broad range of cellular processes. It participates at multiple levels of gene regulation, including DNA replication, transcription, translation, RNA transport, and microRNA processing. It has been implicated in tumorigenesis and recent evidence suggests that it may be a promising chemotherapeutic target. Previous studies have determined that DHX9 suppression elicits an apoptotic or senescence response by activating p53 signaling. Here, we show that DHX9 inhibition can also have deleterious effects in cells lacking functional p53. Loss of DHX9 led to increased cell death in p53-deficient mouse lymphomas and HCT116 human colon cancer cells, and G0/G1 cell cycle arrest in p53-deficient mouse embryonic fibroblasts. Analysis of mRNA levels for p53 transcriptional targets showed that a subset of p53 targets in the p53-null lymphomas and HCT116 cells were activated despite the absence of functional p53. This implies an alternative pathway of DHX9-mediated activation of cell death and cell cycle arrest in p53-deficient cells and supports the feasibility of targeting DHX9 in p53-deficient tumors.
Highlights
DHX9 ( known as Nuclear DNA Helicase II (NDH II) and RNA Helicase A (RHA)) is an NTP-dependent helicase belonging to the DExH-box family of helicase proteins
DHX9 suppression reduces cellular fitness in both p53-wildtype and p53-null settings. Previous studies in both non-transformed cells and tumor models initially suggested that functional p53 signaling is essential for the cell death or senescence response resulting from DHX9 inhibition [16, 17]
We knocked down DHX9 in p53-wildtype and p53-null settings in three different cell types. p53−/−Eμ-Myc lymphomas were compared to TSC2+/−Eμ-Myc lymphomas – the latter of which were previously characterized and shown to contain functional p53 signaling as well as being highly responsive to DHX9 suppression [18,19,20]
Summary
DHX9 ( known as Nuclear DNA Helicase II (NDH II) and RNA Helicase A (RHA)) is an NTP-dependent helicase belonging to the DExH-box family of helicase proteins. DHX9 is a multi-domain protein, consisting of a core helicase domain harboring the conserved DEIH sequence, two RNA-binding domains at the N-terminus, a nuclear transport domain and a DNA-binding RGGbox at the C-terminus [1]. It is capable of unwinding a variety of substrates, including DNA, RNA, and complex polynucleotide structures [2, 3], and has been implicated in many diverse biological processes. Due to the important regulatory role played by DHX9, there is growing evidence of its implications in human diseases such as various cancers and viral infections [15]
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