Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation

Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation. The Ran GTPase plays a key role in mitotic spindle assembly. However, how the generation of a chemical gradient of Ran-GTP at the spindle is coupled to mitotic post-translational modifications has never been characterized. Here, we solved the complex structure of Ran with the nucleotide release factor Mogl and delineated a novel mitosis-specific acetylation-regulated Ran-Mogl interaction dur- ing chromosome segregation. Our structure-guided functional analyses revealed that Mogl compotes with RCCl for Ran binding in a GTP/GDP-dependent manner. Biochemical characterization demonstrated that Mogl-bound Ran prevents RCCl binding and subse- quent GTP loading. Surprisingly, Ran is a bono fide substrate of TIP60, and the acetylation of Lys134 by TIP60 liberates Mogl from Ran binding during mitosis. Importantly, this acetylation-elicited switch of Ran binding to RCC1 promotes high level of Ran-GTP, which is essential for chromosome alignment. These results establish a previously uncharacterized regulatory mechanism in which TIP60 pro- vides a homeostatic control of Ran-GTP level by tuning Ran effector binding for chromosome segregation in mitosis.

LRIF1 interacts with HPla to coordinate accurate chromosome segregation during mitosis

Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Our earlier study showed that centromeric Localization of HP1α depends on the epigenetic mark H3K9me3 in interphase,while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors.Here,we identified a PXVXL-containing protein,Ligand-dependent nuclear receptorinteracting factor 1 (LRIF1),which recruits HPla to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis.LRIF1 interacts directly with HPla chromoshadow domain via an evolutionariLy conserved PXVXL motif within its C-terminus.Importantly,the LRIF1-HPla interaction is critical for Aurora B activity in the inner centromere.Mutation of PXVXL motif of LRIF1 Leads to defects in HPla centromere targeting and aberrant chromosome segregation.These findings reveal a previously unrecognized direct Link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1-HP1α interaction in orchestrating accurate cell division.