rRNA transcription is regulated by sequestering LATS2 and PHF6 to the nuclear speckle following DNA damage

Mammalian large tumor suppressor 2 (LATS2) is an evolutionarily conserved Ser/Thr kinase that regulates the Hippo signaling pathway and cell cycle checkpoints. In this study, we demonstrate that ultraviolet (UV) irradiation causes the phosphorylation of LATS2 at S835, localizing a portion of it to the nuclear speckle, which is a membraneless organelle enriched in pre-mRNA splicing factors in the nucleoplasm. This phosphorylation can potentially enhance LATS2 kinase activity and induce subsequent phosphorylations of plant homeodomain finger protein 6 (PHF6) on S183 site. We also show that LATS2 promotes rRNA transcription in the absence of UV irradiation and that PHF6 is translocated from the nucleolus to the nucleoplasm after UV damage. Some of the phosphorylated PHF6 were localized in the nuclear speckles after UV irradiation, eventually preventing LATS2-mediated rRNA transcription. These results suggest that the nuclear speckle functions as a sequestration site for transcriptional regulators and as a crucible that promotes biochemical reactions in the DNA damage response. Therefore, a strategy targeting the LATS2-PHF6 axis could facilitate the development of new therapies for critical diseases caused by abnormal rRNA synthesis, such as ribosomopathies and cancers.