Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju, 28644, South Korea.
College of Pharmacy, Chungbuk National University, Cheongju, 361-763, South Korea.
Nat Commun. 2019 Apr 23;10(1):1897. doi: 10.1038/s41467-019-09810-w.
The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions.
细胞是否进行增殖或死亡的决定是在限制（R）点做出的，几乎所有肿瘤中这个限制点都被破坏了。控制 R 点决定的分子机制的特征是细胞生物学中的一个基本问题。我们发现，在有丝分裂刺激后早期，RUNX3 与它的靶基因座结合，通过顺序募集转录激活因子和细胞周期调节剂来打开染色质结构，从而将细胞推向 R 点。不久之后，RUNX3 通过招募 Polycomb 抑制复合物来关闭这些基因座，导致细胞通过 R 点进入 S 期。如果 RAS 信号持续激活，RUNX3 通过将与 R 点相关的基因保持在开放结构中来抑制细胞周期的进展。我们的结果确定 RUNX3 是 R 点的先驱因子，并揭示了适当的染色质修饰因子如何被选择性募集到靶基因座以做出适当的 R 点决定的分子机制。
