Monopolar Spindle 1 (MPS1) Protein-dependent Phosphorylation of RecQ-mediated Genome Instability Protein 2 (RMI2) at Serine 112 Is Essential for BLM-Topo III α-RMI1-RMI2 (BTR) Protein Complex Function upon Spindle Assembly Checkpoint (SAC) Activation during Mitosis

Abstract

Background:The BTR complex is required for genomic stability and is posttranslationally modified in cells arrested at the mitotic spindle assembly checkpoint (SAC). Results: We identify serine 112 (Ser-112) as an MPS1-dependent phosphorylation site on RMI2. Conclusion: MPS1-dependent phosphorylation of RMI2 regulates the chromosomal maintenance upon SAC activation during mitosis. Significance: Phosphorylation of RMI2 regulates SAC checkpoint signaling and maintains genomic stability.

Accumulation and Phosphorylation of RecQ-Mediated Genome Instability Protein 1 (RMI1) at Serine 284 and Serine 292 during Mitosis

“…These results suggest RMI1 might have important functions during mitosis. Furthermore, consistent with the recent observation [ 22 ], RMI1 is subject to phosphorylation not only upon mitotic interfering agents, but also during undisturbed mitosis ( Figure 2 ), which indicates RMI1 might have mitosis-specific functions.…”

“…Upon mitosis blocking agents, phosphorylation of BLM at Ser-144 and RMI2 at Ser-112 is completely dependent on the kinase MPS1, while RMI1 phosphorylation only partially depends on MPS1 [ 22 ], suggesting another kinase may be also responsible for mitotic RMI1 phosphorylation. In addition to MPS1, three other kinases, ATM, ATR and CDK1, have been reported to phosphorylate BLM proteins [ 6 , 24 ].…”

“…It has been well established that RMI1 greatly stimulates the BLM-Topo IIIα-mediated double Holliday junction (dHJ) dissolution in homologous recombination, leading exclusively to non-crossover products to prevent sister chromatid exchanges (SCEs) [ 25 , 26 ]. Interestingly, more and more evidence has shown that BLM and RMI2 are required for the maintenance of chromosome stability at the spindle assembly checkpoint (SAC) [ 21 , 22 ]. Moreover, one interesting observation is that the BLM-Topo IIIα-RMI1 complex localizes to DNA bridges and lagging chromatin during anaphase [ 27 ].…”

“…Disruption of the mitotic spindle by microtubule poisons, such as nocodazole, activates the SAC and arrests the cells before anaphase onset. Previous studies demonstrated that both phosphorylation of BLM at S114 and phosphorylation of RMI2 at S112 are essential to maintain mitotic arrest upon SAC activation [ 21 , 22 ]. Since RMI1 associates with BLM regardless of their phosphorylation status at mitosis, it is conceivable that mitotic RMI1 phosphorylation may have similar roles as mitotic BLM phosphorylation in spindle checkpoint.…”

“…At the post-translational modification level, it has been found that BLM and RMI2 are phosphorylated upon spindle assembly checkpoint (SAC) activation, which is dependent on the mitotic kinase monopolar spindle 1 (MPS1). Functionally, phosphorylation of BLM on Ser144 and phosphorylation of RMI2 on Ser112 are important for maintaining mitotic arrest and genomic stability [ 21 , 22 ]. RMI1 is an integral and functional component of the BTR complex [ 12 ].…”