A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage
A Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage
复制标题
DOI：
10.1016/j.cell.2012.01.040
复制
发表时间：
2012-03-02
期刊：
影响因子：
64.5
通讯作者：
Rudolph, K. Lenhard
中科院分区：
文献类型：
--
作者：
Wang, Jianwei;Sun, Qian;Rudolph, K. Lenhard
限制干细胞自我更新以应对DNA损伤的检查点有助于癌症保护，但也可能促进组织衰老。控制干细胞对DNA损伤的反应的分子成分仍有待描述。使用体内RNAi筛选，我们鉴定了碱性亮氨酸拉链转录因子ATF样（BATF）作为限制造血干细胞（HSC）响应端粒功能障碍和g-照射的自我更新的主要成分。DNA损伤以G-CSF/STAT 3依赖的方式诱导BATF，导致HSC的淋巴样分化。BATF缺失改善HSC自我更新和响应g-照射或端粒缩短的功能，但导致HSC中DNA损伤的积累。骨髓增生异常综合征患者的骨髓分析支持DNA损伤依赖性BATF诱导在人HSC中是保守的这一结论。总之，这些结果提供了实验证据，即BATF依赖性分化检查点限制了HSC响应DNA损伤的自我更新。
Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and g-irradiation. DNA damage induces BATF in a G-CSF/ STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to g-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.