French Bradley T, Westhorpe Frederick G, Limouse Charles, Straight Aaron F
Department of Biochemistry, Stanford University, 279 Campus Drive, Beckman 409, Stanford, CA 94305, USA.
Department of Applied Physics, Stanford University, 348 Via Pueblo Mall, Stanford, CA 94305, USA.
Dev Cell. 2017 Jul 24;42(2):190-199.e10. doi: 10.1016/j.devcel.2017.06.021.
Vertebrate centromeres are epigenetically defined by nucleosomes containing the histone H3 variant, CENP-A. CENP-A nucleosome assembly requires the three-protein Mis18 complex (Mis18α, Mis18β, and M18BP1) that recruits the CENP-A chaperone HJURP to centromeres, but how the Mis18 complex recognizes centromeric chromatin is unknown. Using Xenopus egg extract, we show that direct, cell-cycle-regulated binding of M18BP1 to CENP-A nucleosomes recruits the Mis18 complex to interphase centromeres to promote new CENP-A nucleosome assembly. We demonstrate that Xenopus M18BP1 binds CENP-A nucleosomes using a motif that is widely conserved except in mammals. The M18BP1 motif resembles a CENP-A nucleosome binding motif in CENP-C, and we show that CENP-C competes with M18BP1 for CENP-A nucleosome binding at centromeres. We show that both CENP-C and M18BP1 recruit HJURP to centromeres for new CENP-A assembly. This study defines cellular mechanisms for recruiting CENP-A assembly factors to existing CENP-A nucleosomes for the epigenetic inheritance of centromeres.
脊椎动物的着丝粒由包含组蛋白H3变体CENP - A的核小体在表观遗传上定义。CENP - A核小体组装需要三聚体Mis18复合体（Mis18α、Mis18β和M18BP1），该复合体将CENP - A伴侣蛋白HJURP招募到着丝粒，但Mis18复合体如何识别着丝粒染色质尚不清楚。利用非洲爪蟾卵提取物，我们发现M18BP1与CENP - A核小体的直接、细胞周期调控结合将Mis18复合体招募到间期着丝粒，以促进新的CENP - A核小体组装。我们证明非洲爪蟾M18BP1使用一个除哺乳动物外广泛保守的基序结合CENP - A核小体。M18BP1基序类似于CENP - C中的CENP - A核小体结合基序，并且我们表明CENP - C与M18BP1在着丝粒处竞争CENP - A核小体结合。我们表明CENP - C和M18BP1都将HJURP招募到着丝粒以进行新的CENP - A组装。这项研究确定了将CENP - A组装因子招募到现有的CENP - A核小体以实现着丝粒表观遗传遗传的细胞机制。
