Here we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in adult mice led to bone marrow failure whereas parenchymal organs composed of nonproliferating cells were unaffected. Depletion of Ars2 or CBP80 from proliferating cells impaired miRNA-mediated repression and led to alterations in primary miRNA processing in the nucleus. Ars2 depletion also reduced the levels of several miRNAs, including miR-21, let-7, and miR-155, that are implicated in cellular transformation. These findings provide evidence for a role for Ars2 in RNA interference regulation during cell proliferation.
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We thank Zissimos Mourelatos for helpful discussions and providing luciferase reporters. We thank Iain Mattaj for kindly providing CBC antibodies, Ramin Shiekhattar for kindly providing Flag-Dicer and Flag-Drosha plasmids, and Michael Milone for providing a pri-miR-155 plasmid. We thank Jim Alwine, Scott Poethig, and members of the Thompson and Dreyfuss laboratories for discussions and inspiration. J.J.G. and C.B.T. are supported by funds from the NIH and the A.F.C.R.I.