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HASPIN kinase mediates histone deacetylation to regulate oocyte meiotic maturation in pigs. Cao Z et al. (2019) HASPIN kinase-catalyzed phosphorylation of histone H3 on threonine 3 (H3T3p) directs the activity and localization of chromosomal passenger complex (CPC) and spindle assembly checkpoint (SAC) to regulate chromosome condensation and segregation in both mitosis and meiosis. However, the function of HASPIN kinase in the meiotic maturation of porcine oocytes is not yet known. Here, we found that HASPIN mRNA is constantly expressed in porcine oocyte maturation and subsequent early embryo development. H3T3p is highly enriched on chromosomes at germinal vesicle breakdown (GVBD) stage and thereafter maintains a low level in progression through metaphase I (MI) to metaphase II (MII). Correspondingly, H3T3p was completely abolished in oocytes treated with an inhibitor of HASPIN kinase. Functionally, inhibition of HASPIN activity led to a significant reduction in the rate of oocyte meiotic maturation and the limited cumulus expansion. Additionally, HASPIN inhibition caused both spindle disorganization and chromosome misalignment in oocytes at MI and MII stage. Importantly, HASPIN inhibition severely prevented deacetylation of several highly conserved lysine (K) residues of histone H3 and H4 including H3K9, H3K14, H4K5, H4K8, H4K12 and H4K16 on the metaphase chromosomes during oocyte meiotic maturation. Taken together, these results demonstrate that HASPIN kinase regulates porcine oocyte meiotic maturation via modulating histone deacetylation.//////////////////
DNA damage induces a kinetochore-based ATM/ATR-independent SAC arrest unique to the first meiotic division in mouse oocytes. Lane SIR et al. (2017) Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on the spindle assembly checkpoint, which results in anaphase-promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes DNA damage assembles checkpoint proteins at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min. Despite this robust response, there is no measurable loss in k-fibres, or tension across the bivalent. Through pharmacological inhibition we observed the response is dependent on Mps1 kinase, Aurora kinase, and haspin. Using oocyte specific knockouts we find the response does not require the DNA damage response kinases ATM or ATR. Furthermore, checkpoint activation does not occur in response to DNA damage in fully mature eggs during meiosis II, despite the divisions being separated by just a few hours. Therefore, mouse oocytes have a unique ability to sense DNA damage rapidly by activating the checkpoint at their kinetochores.////////////////// TH2A is phosphorylated at meiotic centromere by Haspin. Hada M et al. (2017) Histone phosphorylation is sometimes associated with mitosis and meiosis. We have recently identified a phosphorylation of the 127th threonine on TH2A (pTH2A), a germ cell-specific H2A variant, in condensed spermatids and mitotic early preimplantation embryos of mice. Here, we further report the existence of pTH2A at the centromeres in metaphase I spermatocytes and oocytes. Moreover, we identified Haspin, a known kinase for the 3rd threonine on H3, is responsible for pTH2A in vivo. In contrast to the severe meiotic defect in oocytes treated with a Haspin inhibitor, pTH2A-deficient mice, in which the 127th threonine was replaced by alanine, maintained the fertility and exhibited no obvious defect in both oocytes and spermatogenesis. Interestingly, pTH2A was significantly decreased in aged oocytes, suggesting that its accumulation is regulated by centromeric cohesins. Collectively, our study proposes a new set of kinase-histone pair at meiotic centromere, which is highly coordinated during meiosis.//////////////////
Haspin kinase regulates microtubule-organizing center clustering and stability through Aurora kinase C in mouse oocytes. Balboula AZ et al. (2016) Meiotic oocytes lack classic centrosomes and therefore, bipolar spindle assembly depends on clustering of acentriolar microtubule-organizing centers (MTOCs) into two poles. However, the molecular mechanism regulating MTOCs assembly into two poles is not fully understood. Haspin kinase is required to regulate Aurora kinase C (AURKC) localization at chromosomes during meiosis I (MI). Here we show that inhibition of haspin perturbed MTOC clustering into two poles, and the stability of the clustered MTOCs. Furthermore, we show that AURKC localizes to MTOCs in mouse oocytes. Inhibition of haspin perturbed the localization of AURKC at MTOCs, and overexpression of AURKC rescued the MTOC clustering defects in haspin-inhibited oocytes. Taken together, our data uncover a role for haspin as a regulator of bipolar spindle assembly by regulating AURKC localized-function at acentriolar MTOCs in oocytes.//////////////////
Phosphorylation of threonine 3 on histone H3 by haspin kinase is required for meiosis I in mouse oocytes. Nguyen AL et al. (2014) Meiosis I (MI), the division that generates haploids, is prone to errors that lead to aneuploidy in females. Haspin is a kinase that phosphorylates histone H3 on threonine 3, thereby recruiting Aurora kinase B (AURKB) and the chromosomal passenger complex (CPC) to kinetochores to regulate mitosis. Haspin and AURKC, an AURKB homolog, are enriched in germ cells, yet their significance in regulating MI is not fully understood. Using inhibitors and overexpression approaches, we show a role for haspin during MI in mouse oocytes. Haspin-perturbed oocytes display abnormalities in chromosome morphology and alignment, improper kinetochore-microtubule attachments at metaphase I and aneuploidy at metaphase II. Unlike in mitosis, kinetochore localization remained intact, whereas the distribution of the CPC along chromosomes was absent. The meiotic defects following haspin inhibition were similar to those observed in oocytes where AURKC was inhibited, suggesting that the correction of microtubule attachments during MI requires AURKC along chromosome arms rather than at kinetochores. Our data implicate haspin as a regulator of the CPC and chromosome segregation during MI, while highlighting important differences in how chromosome segregation is regulated between MI and mitosis.//////////////////
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