Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive.Here we have identified meiosis-specific kinetochore factor MEIKIN in mouse, which functions in meiosis I but neither in meiosis II nor in mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated largely by the activity of Polo-like kinase PLK1, which is enriched to kinetochores depending on MEIKIN. Our integrative analysis indicates that MEIKIN is the long awaited key regulator of meiotic kinetochore function, which is conserved from yeasts to humans. 2In mitosis, sister chromatid cohesion is established depending on cohesin in S phase and maintained until metaphase when the sister chromatids are captured by spindle microtubules from opposite poles and aligned on the spindle equator. For the onset of anaphase, the anaphase-promoting complex (APC) triggers the degradation of securin, an inhibitory chaperone for separase that cleaves cohesin RAD21 and removes cohesin along the entire chromosome. This removal of cohesin triggers the separation of sister chromatids and their movement to opposite poles, a process called equational division [1][2][3] . During meiosis, however, meiotic cohesin REC8 largely replaces RAD21 along the entire chromosomes; one round of DNA replication is followed by two rounds of nuclear division, which results in four haploid nuclei or gametes (Fig. 1a).In the first division of meiosis (meiosis I), homologous chromosomes connected by chiasmata are captured from the opposite poles, while sisters are captured from the same pole (mono-orientation). At the onset of anaphase I, REC8 cohesin is cleaved by separase along the arm regions, but protected at centromeres until metaphase II 4-6 . Thus, mono-orientation and centromeric cohesion protection are two hallmarks of meiotic kinetochore function, which are widely conserved among eukaryotic organisms 7-9 (Fig. 1a). There is accumulating evidence that cohesion protection is mediated by the centromeric protein shugoshin (SGO) and its partner protein phosphatase 2A (PP2A) [10][11][12][13][14][15] , which antagonizes REC8 phosphorylation, a prerequisite of cleavage 16, 17 . So far, meiosis-specific kinetochore proteins have been identified only in two yeasts (S. cerevisiae Spo13 and Mam1 (monopolin subunit), and S. pombe Moa1) [18][19][20][21][22][23] . Puzzlingly, however, because their structural and functional similarities remain to be identified, conservation of meiotic kinetochore regulation is questionable even between yeasts 8, 9 . Therefore, in this study, we address the long-standing question of whether meiotic kinetochore regulation is conserved from yeasts to mammals, and, if so, how. Mammalian meiotic kinetochore protein MEIKINFission yeast Moa1 interacts directly with the conserved kinetochore protein Cnp3 (CENP-C homolog), and localizes to the kinetochore in meiosis I 24 . To identify an equivalent meiosis...

During meiosis, the cohesin complexes that maintain sister chromatid cohesion are lost in a stepwise manner. At meiosis I the cohesin subunit Rec8 is cleaved only along the chromosome arms; until meiosis II it is protected at centromeres by the action of shugoshin (Sgo1)-protein phosphatase 2A (PP2A). Although this regulation hypothetically involves phosphorylation that is antagonized by Sgo1-PP2A, the kinase and substrate that are responsible are as yet unknown. Using a genetic screen for 'anti-shugoshin', we identify Hhp2, an orthologue of casein kinase 1delta/epsilon (CK1), as a factor required for Rec8 cleavage in fission yeast. We show that CK1, rather than a Polo-like kinase that is widely believed to do so, acts as the cohesin kinase to promote this cleavage during meiosis. Crucially, forced localization of excess Hhp2 at the pericentromeric region abrogates the ability of Sgo1-PP2A to protect centromeric Rec8. Thus, our studies prove the key notion that the balance between Rec8 phosphorylation and its dephosphorylation by Sgo1-PP2A regulates the step-wise loss of chromosomal cohesion in meiosis.

In meiosis I, sister chromatids are captured by microtubules emanating from the same pole (mono‐orientation), and centromeric cohesion is protected throughout anaphase. Shugoshin, which is localized to centromeres depending on the phosphorylation of histone H2A by Bub1 kinase, plays a central role in protecting meiotic cohesin Rec8 from separase cleavage. Another key meiotic kinetochore factor, meikin, may regulate cohesion protection, although the underlying molecular mechanisms remain elusive. Here, we show that fission yeast Moa1 (meikin), which associates stably with CENP‐C during meiosis I, recruits Plo1 (polo‐like kinase) to the kinetochores and phosphorylates Spc7 (KNL1) to accumulate Bub1. Consequently, in contrast to the transient kinetochore localization of mitotic Bub1, meiotic Bub1 persists at kinetochores until anaphase I. The meiotic Bub1 pool ensures robust Sgo1 (shugoshin) localization and cohesion protection at centromeres by cooperating with heterochromatin protein Swi6, which binds and stabilizes Sgo1. Furthermore, molecular genetic analyses show a hierarchical regulation of centromeric cohesion protection by meikin and shugoshin that is important for establishing meiosis‐specific chromosome segregation. We provide evidence that the meiosis‐specific Bub1 regulation is conserved in mouse.

Our research provides an approach to synthetically modulating histone posttranslational modifications without relying on endogenous enzymes. We have developed an artificial catalyst system comprising nucleosome-binding catalysts and acyl donors. The catalyst system preferentially acylates lysines on histone tails and modulates chromatin structure similarly to histone acetyltransferases. Our system can be a useful tool for studying chromatin-modification enzymes as well as the functions of histone acylations.