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  • Whereas Sororin is dispensable in the absence of Wapl overex

    2022-06-15

    Whereas Sororin is dispensable in the absence of Wapl [14], overexpressed Haspin only partly supports cohesion in Sororin-depleted cells. Thus, although Haspin and Sororin have functional similarities, they are not fully redundant at the centromere. Haspin may have a mitosis-specific role in maintaining centromeric cohesion due to its conformation change and activation during mitotic entry [34, 46]. Alternatively, Sororin may have a YSR-motif-independent activity in binding Pds5 [14] or other cohesin subunits [45, 47] to protect cohesion. We suggest that whereas Sororin plays a dual role in cohesion establishment and maintenance [48, 49, 50], Haspin is needed to compensate for the removal of Sororin from mitotic centromeres when Sororin undergoes strong phosphorylation in early mitosis. One may wonder why Haspin-KO bafilomycin do not show strong cohesion defects during unperturbed mitosis and are viable. There might be distinct pools of centromeric cohesin complexes in which Pds5B binds to either Haspin or Sororin. In the absence of Haspin, the Sororin-containing cohesin complex may be able to sustain the minimal strength of centromeric cohesion to prevent lethality without additional perturbation on mitosis but insufficient to resist the sustained pulling forces generated by the mitotic spindle. Alternatively, using the similar Pds5-binding motif, Sororin, or even other centromeric proteins, has partially compensated the loss of Haspin-Wapl antagonism in the Haspin mutant cell lines. Moreover, as Gimenez-Abian et al. suggested that “in unperturbed mitoses, arm cohesion nevertheless persists throughout metaphase and is [in principle] sufficient to maintain sister chromatid cohesion” [3, 8], selective disruption of the pathway protecting centromeric cohesin may not cause strong cohesion defects in unperturbed mitosis. Indeed, cells lacking Haspin-Pds5B interaction are particularly defective in tolerating prolonged mitosis, which allows time for further disassociation of cohesin from chromosome arms (Figure S7). We also reason that lack of apparent prophase pathway might account for the previous observation that Hrk1 is dispensable for cohesion in fission yeast [24]. Regardless, defects that moderately impair chromosome segregation may allow cancer cells with chromosomal instability (CIN) to become established [39]. The partial functional redundancy between Haspin and Sororin in protecting centromeric cohesion makes Haspin an appealing candidate whose inactivation may lead to CIN in tumor cells. H3pT3 by Haspin promotes the inner centromeric localization of CPC to allow proper kinetochore-microtubule (KT-MT) attachments [24, 25, 26, 30, 31, 33]. Here we show that Haspin also plays a direct role in protecting centromeric cohesion through binding to Pds5B. Thus, Haspin is required for both proper KT-MT attachments and sister-chromatid cohesion. Whether Haspin kinase activity also contributes to centromeric cohesion protection requires further study. Our study helps rationalize the apparent complexity of the centromere signaling network and may have broader implications for the understanding of chromosome dynamics during mitosis.
    Experimental Procedures Experimental procedures and any associated references are available in the Supplemental Information.
    Author Contributions
    Acknowledgments We thank Drs. Jonathan Higgins and Xiangwei He for critical reading and commenting on the manuscript and Drs. Hongtao Yu and David Spector for kindly providing reagents. This work was supported by grants to F.W. from the National Natural Science Foundation of China (NSFC; 31322032, 31371359, 31571393, and 31561130155), a National Thousand Young Talents Award, the Natural Science Foundation of Zhejiang Province (LR13C070001 to F.W. and LY17C070003 to H.Y.), the Fundamental Research Funds for the Central Universities (2014XZZX003-35), the Zhejiang University K.P. Chao’s High Technology Development Foundation (2013RC022), and a grant from the NSFC to S.Y. (31370721).