Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage.
Diminished apoptotic priming and ATM signalling confer a survival advantage onto aged haematopoietic stem cells in response to DNA damage.
复制标题
凋亡启动和 ATM 信号传导的减弱赋予衰老造血干细胞响应 DNA 损伤的生存优势。
DOI：
10.1038/s41556-018-0054-y
复制
发表时间：
2018-04
影响因子：
21.3
通讯作者：
Rossi DJ
中科院分区：
文献类型：
--
作者：
Gutierrez-Martinez P;Hogdal L;Nagai M;Kruta M;Singh R;Sarosiek K;Nussenzweig A;Beerman I;Letai A;Rossi DJ
造血干细胞（HSC）的老化导致老年造血系统的缺陷。HSC的衰退部分是由DNA损伤积累驱动的，但衰老如何影响HSC的急性DNA损伤反应（DDR）尚不清楚。我们发现，老年HSC表现出减少ATM活性和衰减DDR导致克隆存活率升高，以应对一系列由减少凋亡引发所承保的基因毒素。不同的HSC亚群表现出年龄依赖性和亚型依赖性的差异，凋亡启动和生存的DNA损伤。有缺陷的DDR的老HSC是非细胞自主的ATM信号，并响应于DNA损伤的克隆存活可以恢复到年轻的HSC移植到年轻的受体后观察到的水平。这些数据表明，有缺陷的DDR和减少的凋亡引发提供了一个选择性的优势，老HSC，可能有助于突变的积累和疾病的易感性。
Ageing of haematopoietic stem cells (HSC) contributes to deficits in the aged haematopoietic system. HSC decline is driven in part by DNA damage accumulation, yet how aging impacts the acute DNA damage response (DDR) of HSCs is poorly understood. We show that old HSCs exhibit diminished ATM activity and attenuated DDR leading to elevated clonal survival in response to a range of genotoxins that was underwritten by diminished apoptotic priming. Distinct HSC subsets exhibited ageing-dependent and subtype-dependent differences in apoptotic priming and survival in response to DNA damage. The defective DDR of old HSCs was non-cell autonomous as ATM signalling, and clonal survival in response to DNA damage could be restored to levels observed in young HSCs post-transplantation into young recipients. These data suggest that defective DDR and diminished apoptotic priming provide a selective advantage to old HSCs that may contribute to mutation accrual and disease predisposition.