Heterochromatin protein‐1 (HP1) is a key component of heterochromatin. Reminiscent of the cohesin complex which mediates sister‐chromatid cohesion, most HP1 proteins in mammalian cells are displaced from chromosome arms during mitotic entry, whereas a pool remains at the heterochromatic centromere region. The function of HP1 at mitotic centromeres remains largely elusive. Here, we show that double knockout (DKO) of HP1α and HP1γ causes defective mitosis progression and weakened centromeric cohesion. While mutating the chromoshadow domain (CSD) prevents HP1α from protecting sister‐chromatid cohesion, centromeric targeting of HP1α CSD alone is sufficient to rescue the cohesion defects in HP1 DKO cells. Interestingly, HP1‐dependent cohesion protection requires Haspin, an antagonist of the cohesin‐releasing factor Wapl. Moreover, HP1α CSD directly binds the N‐terminal region of Haspin and facilitates its centromeric localization. The need for HP1 in cohesion protection can be bypassed by centromeric targeting of Haspin or inhibiting Wapl activity. Taken together, these results reveal a redundant role for HP1α and HP1γ in the protection of centromeric cohesion through promoting Haspin localization at mitotic centromeres in mammalian cells. Synopsis Sister‐chromatid cohesion must be properly regulated to prevent chromosome mis‐segregation and chromosomal instability. HP1 proteins bind to the cohesin protector Haspin and promote its centromeric localization, thereby protecting cohesion at mitotic centromeres. HP1α and HP1γ play redundant roles in protecting mitotic centromeric cohesion in mammals. HP1α binds Haspin to promote its centromeric localization, inhibiting Wap1‐mediated cohesin release. HP1 proteins link centromeric heterochromatin to sister‐chromatid cohesion.

The key mitotic regulator Polo-like kinase 1 (Plk1) is activated during G2 phase by Aurora A kinase (AurkA)-mediated phosphorylation of its activation loop, which is important for timely mitotic entry. The mechanism for Plk1 activation remains incompletely understood. Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. These defects are rescued by exogenous expression of wild-type WAC, but not the Plk1-binding-deficient mutant. WAC also binds AurkA and can enhance Plk1 phosphorylation by AurkA in vitro. Taken together, these results indicate an important role for WAC in promoting Plk1 activation and the timely entry into mitosis.

The transcriptional regulator ATRX, a genetic factor, is associated with a range of disabilities, including intellectual, hematopoietic, skeletal, facial, and urogenital disabilities. ATRX mutations substantially contribute to the pathogenesis of ATRX syndrome and are frequently detected in gliomas and many other cancers. These mutations disrupt the organization, subcellular localization, and transcriptional activity of ATRX, leading to chromosomal instability and affecting interactions with key regulatory proteins such as DAXX, EZH2, and TERRA. ATRX also functions as a transcriptional regulator involved in the pathogenesis of neuronal disorders and various diseases. In conclusion, ATRX is a central protein whose abnormalities lead to multiple diseases.