McKenney Connor, Lendner Yovel, Guerrero Zuniga Adler, Sinha Niladri, Veresko Benjamin, Aikin Timothy J, Regot Sergi
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Science. 2024 May 3;384(6695):eadi2421. doi: 10.1126/science.adi2421.
Cell cycle events are coordinated by cyclin-dependent kinases (CDKs) to ensure robust cell division. CDK4/6 and CDK2 regulate the growth 1 (G) to synthesis (S) phase transition of the cell cycle by responding to mitogen signaling, promoting E2F transcription and inhibition of the anaphase-promoting complex. We found that this mechanism was still required in G-arrested cells to prevent cell cycle exit after the S phase. This mechanism revealed a role for CDK4/6 in maintaining the G state, challenging the notion that the cell cycle is irreversible and that cells do not require mitogens after passing the restriction point. Exit from G occurred during ribotoxic stress and was actively mediated by stress-activated protein kinases. Upon relief of stress, a significant fraction of cells underwent a second round of DNA replication that led to whole-genome doubling.
细胞周期事件由细胞周期蛋白依赖性激酶（CDK）协调，以确保强大的细胞分裂。CDK4/6和CDK2通过响应有丝分裂原信号、促进E2F转录和抑制后期促进复合物来调节细胞周期从生长1（G）期到合成（S）期的转变。我们发现，在G期停滞的细胞中，该机制对于防止S期后细胞周期退出仍然是必需的。这一机制揭示了CDK4/6在维持G期状态中的作用，挑战了细胞周期是不可逆的以及细胞在通过限制点后不需要有丝分裂原的观念。在核糖体毒性应激期间发生了从G期退出，并且由应激激活的蛋白激酶积极介导。应激缓解后，相当一部分细胞经历了第二轮DNA复制，导致全基因组加倍。
