Abstract
Regulated interactions between kinetochores and spindle microtubules are critical for maintaining genomic stability during chromosome segregation. Defects in chromosome segregation are widespread phenomenon in human cancers that are thought to serve as the fuel for tumorigenic progression. Tumor suppressor proteins ASPP1 and ASPP2, two members of the apoptosis stimulating proteins of p53 (ASPP) family, are frequently down-regulated in human cancers. Here we report that ASPP1/2 are required for proper mitotic progression. In ASPP1/2 co-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in persistent spindle assembly checkpoint (SAC) activation. Using protein affinity purification methods, we searched for functional partners of ASPP1/2, and found that ASPP1/2 were associated with a subset of kinetochore proteins (Hec1, KNL-1, and CENP-F). It was found that ASPP1/2 act as PP1-targeting subunits to facilitate the interaction between PP1 and Hec1, and catalyze Hec1 (Ser165) dephosphorylation during late mitosis. These observations revealed a previously unrecognized function of ASPP1/2 in chromosome segregation and kinetochore-microtubule attachments that likely contributes to their roles in chromosome stability and tumor suppression.
Highlights
Accurate chromosome segregation requires that all sister chromatids are correctly attached to microtubules emanating from opposite poles before sister chromatids separate
Non-specific binding proteins identified in MOCK HeLa cells were omitted from the list of those identified in FH-ASPP1/HeLa or FH-ASPP2/HeLa cells (Figure 1a and 1b; Table S1 and S2)
Since previous study showed ASPP2 can facilitate the interaction between TAZ and PP1α to promote TAZ dephosphorylation at Ser89 and Ser311 [19], we investigated whether ASPP1/2 act as molecular adaptors to facilitate the interaction between Hec1 and PP1α
Summary
Accurate chromosome segregation requires that all sister chromatids are correctly attached to microtubules emanating from opposite poles (bipolar attachment) before sister chromatids separate. Phosphorylation of substrates at kinetochores destabilizes incorrect attachments, and resets the kinetochore to provide a new opportunity to bi-orient. This process requires that substrates are subsequently dephosphorylated to stabilize correct attachments [6]. The yeast protein Fin and kinetochore protein KNL1 have been identified to target some PP1 to yeast and vertebrate kinetochores, respectively [2, 9]. Another two PP1-targeting subunits, Sds and Repo-Man, stabilize chromosome segregation by counteracting Aurora B on anaphase kinetochores [10]
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