Hammond Taylar, Choi Jong Bin, Membreño Miles W, Demeter Janos, Ng Roy, Bhattacharya Debadrita, Nguyen Thuyen N, Hartmann Griffin G, Bossard Carine, Skotheim Jan M, Jackson Peter K, Pasca Anca, Rubin Seth M, Sage Julien
bioRxiv. 2024 Dec 11:2024.12.10.627280. doi: 10.1101/2024.12.10.627280.
A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified the poorly-studied factor FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the CyclinD-CDK4/6-RB axis in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. DYRK1A kinase inhibition rescues the G1 arrest induced by FAM53C knock-down. Consistent with the role for FAM53C identified in cells in culture, knockout human cortical organoids display increased cell cycle arrest and growth defects. In addition, knockout mice show defects in body growth and behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.
越来越多的疗法正在研发中，旨在针对细胞周期机制来治疗癌症和其他人类疾病。因此，更深入地了解调节细胞周期进程的因素对于提高对这些新疗法的反应至关重要。在此，我们利用癌症依赖性图谱的数据，将研究较少的因子FAM53C鉴定为细胞周期进程的新调节因子。我们发现FAM53C对这种细胞周期转变至关重要，并且在G1/S转变的调控中，它在细胞周期蛋白D - 细胞周期蛋白依赖性激酶4/6 - 视网膜母细胞瘤蛋白（CyclinD-CDK4/6-RB）轴的上游发挥作用。通过质谱分析、生化分析和细胞分析，我们鉴定并验证了双重特异性酪氨酸磷酸化调节激酶1A（DYRK1A）为一种细胞周期激酶，它受到FAM53C的抑制并与之直接相互作用。抑制DYRK1A激酶可挽救因FAM53C敲低诱导的G1期阻滞。与在培养细胞中鉴定出的FAM53C的作用一致，敲除人类皮质类器官显示出细胞周期阻滞增加和生长缺陷。此外，敲除小鼠表现出身体生长和行为表型方面的缺陷。由于DYRK1A失调会导致诸如唐氏综合征等发育障碍以及肿瘤发生，未来旨在调节FAM53C活性的策略可能会使广泛的患者受益。
