A variety of human genetic diseases is known to be caused by mutations in genes encoding chromatin factors and epigenetic regulators, such as DNA or histone modifying enzymes and members of ATP-dependent chromatin remodeling complexes. Floating-Harbor syndrome is a rare genetic disease affecting human development caused by dominant truncating mutations in the SRCAP gene, which encodes the ATPase SRCAP, the core catalytic subunit of the homonymous chromatin-remodeling complex. The main function of the SRCAP complex is to promote the exchange of histone H2A with the H2A.Z variant. According to the canonical role played by the SRCAP protein in epigenetic regulation, the Floating-Harbor syndrome is thought to be a consequence of chromatin perturbations. However, additional potential physiological functions of SRCAP have not been sufficiently explored. We combined cell biology, reverse genetics, and biochemical approaches to study the subcellular localization of the SRCAP protein and assess its involvement in cell cycle progression in HeLa cells. Surprisingly, we found that SRCAP associates with components of the mitotic apparatus (centrosomes, spindle, midbody), interacts with a plethora of cytokinesis regulators, and positively regulates their recruitment to the midbody. Remarkably, SRCAP depletion perturbs both mitosis and cytokinesis. Similarly, DOM-A, the functional SRCAP orthologue in Drosophila melanogaster, is found at centrosomes and the midbody in Drosophila cells, and its depletion similarly affects both mitosis and cytokinesis. Our findings provide first evidence suggesting that SRCAP plays previously undetected and evolutionarily conserved roles in cell division, independent of its functions in chromatin regulation. SRCAP may participate in two different steps of cell division: by ensuring proper chromosome segregation during mitosis and midbody function during cytokinesis. Moreover, our findings emphasize a surprising scenario whereby alterations in cell division produced by SRCAP mutations may contribute to the onset of Floating-Harbor syndrome.

中文翻译：

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ATPase SRCAP 与有丝分裂器相关，揭示了浮港综合征的新分子方面

已知多种人类遗传疾病是由编码染色质因子和表观遗传调节因子的基因突变引起的，例如 DNA 或组蛋白修饰酶和 ATP 依赖性染色质重塑复合物的成员。浮港综合征是一种影响人类发育的罕见遗传疾病，由 SRCAP 基因的显性截短突变引起，该基因编码 ATP 酶 SRCAP，同名染色质重塑复合物的核心催化亚基。SRCAP 复合物的主要功能是促进组蛋白 H2A 与 H2A.Z 变体的交换。根据 SRCAP 蛋白在表观遗传调控中的典型作用，浮港综合征被认为是染色质扰动的结果。然而，SRCAP 的其他潜在生理功能尚未得到充分探索。我们结合细胞生物学、反向遗传学和生化方法来研究 SRCAP 蛋白的亚细胞定位，并评估其参与 HeLa 细胞的细胞周期进程。令人惊讶的是，我们发现 SRCAP 与有丝分裂装置的组件（中心体、纺锤体、中间体）相关，与大量胞质分裂调节剂相互作用，并正向调节它们向中间体的募集。值得注意的是，SRCAP 消耗会干扰有丝分裂和胞质分裂。类似地，DOM-A，黑腹果蝇中的功能性 SRCAP 直系同源物，存在于果蝇细胞的中心体和中间体，其消耗同样影响有丝分裂和胞质分裂。我们的研究结果提供了第一个证据，表明 SRCAP 在细胞分裂中发挥着以前未被发现和进化上保守的作用，独立于其在染色质调节中的功能。SRCAP 可能参与细胞分裂的两个不同步骤：通过确保有丝分裂期间适当的染色体分离和胞质分裂期间的中间体功能。此外，我们的研究结果强调了一个令人惊讶的情况，即由 SRCAP 突变产生的细胞分裂改变可能导致浮港综合征的发作。