Charu Mehta, Isabela Fraga de Andrade, Daniel R Matson, Colin N Dewey, and Emery H Bresnick
Nucleic Acids Research, gkab367, doi:10.1093/nar/gkab367
The RNA exosome complex (EC) mediates processing and/or degradation of select RNAs. During erythropoiesis, the erythroid transcription factor GATA1 represses EC subunit genes. Depleting EC structural subunits prior to GATA1-mediated repression is deleterious to erythroid progenitor cells. Depletion of EC catalytic subunits Dis3 or Exosc10 in hematopoietic progenitor cells reduced erythroid progenitors and their progeny. Dis3 loss compromised erythroid progenitor and erythroblast survival, rendered erythroblasts hypersensitive to apoptosis and induced γ-H2AX, indicative of DNA double-stranded breaks. Dis3 loss-of-function phenotypes were more severe than those caused by Exosc10 depletion. The authors used a genetic rescue system to compare human Dis3 with myeloma-associated Dis3 mutants S447R and R750K. Only wild type Dis3 was competent to rescue progenitors. Dis3 establishes a disease mutation-sensitive, cell type-specific survival mechanism to enable a differentiation program.