Chk1 and Mps1 jointly regulate correction of merotelic kinetochore attachments

Abstract

SummaryIf uncorrected, merotelic kinetochore attachments can induce mis-segregated chromosomes in anaphase. We show that checkpoint kinase 1 (Chk1) protects vertebrate cells against merotelic attachments and lagging chromosomes and is required for correction of merotelic attachments during a prolonged metaphase. Decreased Chk1 activity leads to hyper-stable kinetochore microtubules, unstable binding of MCAK, Kif2b and Mps1 to centromeres or kinetochores and reduced phosphorylation of Hec1 by Aurora-B. Phosphorylation of Aurora-B at serine 331 (Ser331) by Chk1 is high in prometaphase and decreases significantly in metaphase cells. We propose that Ser331 phosphorylation is required for optimal localization of MCAK, Kif2b and Mps1 to centromeres or kinetochores and for Hec1 phosphorylation. Furthermore, inhibition of Mps1 activity diminishes initial recruitment of MCAK and Kif2b to centromeres or kinetochores, impairs Hec1 phosphorylation and exacerbates merotelic attachments in Chk1-deficient cells. We propose that Chk1 and Mps1 jointly regulate Aurora-B, MCAK, Kif2b and Hec1 to correct merotelic attachments. These results suggest a role for Chk1 and Mps1 in error correction.

Dynamic Autophosphorylation of Mps1 Kinase Is Required for Faithful Mitotic Progression

“…Although chromosome congression is normal in the presence of MG132, the high frequency of lagging chromosome observed in Mps1 8D expressing cells indicates the presence of uncorrected merotelic attachments. Recent evidence suggests that Mps1 plays a key role in the correction of merotelic attachment [49]. Consistent with this notion, decreased kinetochore localization of Mps1 8D may induce merotelic attachments.…”

Chk1 protects against chromatin bridges by constitutively phosphorylating BLM serine 502 to inhibit BLM degradation

“…S2D,E). This is a cell system we have previously used for conditional expression of proteins (Petsalaki et al, 2011;Petsalaki and Zachos, 2013). S502D, but not WT, GFP-BLM localised to chromatin bridges in Chk1-deficient cells and accumulated to similar levels in the absence or presence of the Chk1 inhibitor UCN-01 ( Fig.…”

“…Chk1 phosphorylates Aurora B S331 to induce Aurora B catalytic activity and promote correction of mis-attached kinetochores (Petsalaki et al, 2011;Petsalaki and Zachos, 2013). Chk1 also phosphorylates BLM S646 to increase BLM localisation to promyelocytic leukaemia protein (PML) nuclear bodies and regulates BLM accumulation during replication stress through an undescribed mechanism (Sengupta et al, 2004).…”

Chk2 prevents mitotic exit when the majority of kinetochores are unattached

“…Mps1 enhances Aurora B kinase activity according to a certain study (Jelluma et al, 2008), and Aurora B activity is required for efficient recruitment of Mps1 to unattached kinetochores (Hewitt et al, 2010; Maciejowski et al, 2010; Santaguida et al, 2010; Saurin et al, 2011). In addition, Mps1 and Aurora B jointly regulate correction of erroneous kinetochore–microtubule attachments (Petsalaki and Zachos, 2013).…”