Department of Molecular Cell Biology, Institut für Biologie, Humboldt-Universität zu Berlin, 10099 Berlin, Germany.
Department of Molecular Cell Biology, Institut für Biologie, Humboldt-Universität zu Berlin, 10099 Berlin, Germany
Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5386-5393. doi: 10.1073/pnas.1917814117. Epub 2020 Feb 20.
The AAA ATPase and bromodomain factor ATAD2/ANCCA is overexpressed in many types of cancer, but how it contributes to tumorigenesis is not understood. Here, we report that the homolog Yta7 is a deposition factor for the centromeric histone H3 variant Cse4 at the centromere in yeast. Yta7 regulates the levels of centromeric Cse4 in that causes reduced Cse4 deposition, whereas overexpression causes increased Cse4 deposition. Yta7 coimmunoprecipitates with Cse4 and is associated with the centromere, arguing for a direct role of Yta7 in Cse4 deposition. Furthermore, increasing centromeric Cse4 levels by overexpression requires the activity of Scm3, the centromeric nucleosome assembly factor. Importantly, Yta7 interacts in vivo with Scm3, indicating that Yta7 is a cochaperone for Scm3 The absence of Yta7 causes defects in growth and chromosome segregation with mutations in components of the inner kinetochore (CTF19/CCAN, Mif2, Cbf1). Since Yta7 is an AAA ATPase and potential hexameric unfoldase, our results suggest that it may unfold the Cse4 histone and hand it over to Scm3 for subsequent deposition in the centromeric nucleosome. Furthermore, our findings suggest that ATAD2 overexpression may enhance malignant transformation in humans by misregulating centromeric CENP-A levels, thus leading to defects in kinetochore assembly and chromosome segregation.
AAA ATP 酶和溴结构域因子 ATAD2/ANCCA 在许多类型的癌症中过表达，但它如何促进肿瘤发生尚不清楚。在这里，我们报告说同源物 Yta7 是酵母着丝粒处中心体组蛋白 H3 变体 Cse4 的沉积因子。Yta7 调节着丝粒处中心体 Cse4 的水平，因为它导致 Cse4 沉积减少，而 过表达导致 Cse4 沉积增加。Yta7 与 Cse4 共免疫沉淀，并与着丝粒相关，这表明 Yta7 在 Cse4 沉积中具有直接作用。此外，通过 过表达增加中心体 Cse4 水平需要中心体核小体组装因子 Scm3 的活性。重要的是，Yta7 在体内与 Scm3 相互作用，表明 Yta7 是 Scm3 的共伴侣。Yta7 的缺失导致与内着丝粒组件（CTF19/CCAN、Mif2、Cbf1）突变相关的生长和染色体分离缺陷。由于 Yta7 是一个 AAA ATP 酶和潜在的六聚体展开酶，我们的结果表明它可能展开 Cse4 组蛋白并将其递交给 Scm3 以随后沉积在着丝粒核小体中。此外，我们的研究结果表明，ATAD2 过表达可能通过错误调节着丝粒 CENP-A 水平而增强人类的恶性转化，从而导致动粒组装和染色体分离缺陷。
