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AAA+ Proteins RUVBL1 and RUVBL2 Coordinate PIKK Activity and Function in Nonsense-Mediated mRNA Decay

Two ATPases regulate molecular complexes that ensure genome integrity and accurate gene expression. Masters of Integrity In order to survive and faithfully reproduce, cells must not only maintain the integrity of their genome but also regulate the expression of the encoded products, ensure the quality of the transcripts, and coordinate protein production with metabolic status. Members of the phosphatidylinositol 3-kinase–related protein kinase (PIKK) family play essential roles in the DNA- and RNA-based processes that ensure genome integrity and accurate gene expression. Izumi et al. show that the two members of the AAA+ family of proteins, RUVBL1 and RUVBL2, which form a complex involved in chromatin-based processes, also regulated the activity and abundance of all members of the PIKK family. Furthermore, through an interaction with the PIKK member SMG-1, RUVBL1 and RUVBL2 contributed to the formation of macromolecular complexes involved in nonsense-mediated decay, a process by which prematurely terminated mRNA transcripts are eliminated to ensure that potentially dangerous truncated proteins are not produced. Phosphatidylinositol 3-kinase–related protein kinase (PIKK) family proteins play essential roles in DNA-based and RNA-based processes, such as the response to DNA damage, messenger RNA (mRNA) quality control, transcription, and translation, where they contribute to the maintenance of genome integrity and accurate gene expression. The adenosine triphosphatases associated with diverse cellular activities (AAA+) family proteins RuvB-like 1 (RUVBL1) and RUVBL2 are involved in various cellular processes, including transcription, RNA modification, DNA repair, and telomere maintenance. We show that RUVBL1 and RUVBL2 associate with each PIKK family member. We also show that RUVBL1 and RUVBL2 control PIKK abundance at least at the mRNA level. Knockdown of RUVBL1 or RUVBL2 decreased PIKK abundance and impaired PIKK-mediated signaling. Analysis of SMG-1, a PIKK family member involved in nonsense-mediated mRNA decay (NMD), revealed an essential role for RUVBL1 and RUVBL2 in NMD. RUVBL1 and RUVBL2 associated with SMG-1 and the messenger ribonucleoproteins in the cytoplasm and promoted the formation of mRNA surveillance complexes during NMD. Thus, RUVBL1 and RUVBL2 regulate PIKK functions on two different levels: They control the abundance of PIKKs, and they stimulate the formation of PIKK-containing molecular complexes, such as those involved in NMD.