Xpg limits the expansion of haematopoietic stem and progenitor cells after ionising radiation.
Xpg limits the expansion of haematopoietic stem and progenitor cells after ionising radiation.
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DOI：
10.1093/nar/gkw376
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发表时间：
2016-07-27
影响因子：
14.9
通讯作者：
Burkhalter MD
中科院分区：
文献类型：
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作者：
Avila AI;Illing A;Becker F;Maerz LD;Morita Y;Philipp M;Burkhalter MD
基因组维护能力的降低对任何生物体来说都是一个问题，可能导致过早死亡、致癌或加速衰老。但引人注目的是，某些基因组稳定因子的丧失可能是有益的，特别是对于维持肠道和造血系统的组织干细胞而言。因此，我们筛选了在电离辐射（IR）背景下对造血干细胞（HSC）维持产生负面影响的基因组稳定性因素。我们发现，体内敲低着色性干皮病互补组 G (Xpg) 会导致 IR 治疗后 HSC 数量升高，而造血祖细胞数量升高程度较小。 IR 在 mRNA 和蛋白质水平上快速诱导 Xpg。预防这种诱导不会影响检查点级联的激活，但会减弱后期检查点步骤，例如 p21 和 Noxa 的诱导。这会导致细胞周期停滞和细胞凋亡水平降低，两者都有助于增加集落形成和转化率。因此，Xpg 有助于在 IR 后充分诱导 DNA 损伤反应，从而控制受损细胞的扩张。这代表了 Xpg 除了在核苷酸切除修复中的明确作用之外，还在 IR 响应中发挥了新功能。
Reduced capacity of genome maintenance represents a problem for any organism, potentially causing premature death, carcinogenesis, or accelerated ageing. Strikingly though, loss of certain genome stability factors can be beneficial, especially for the maintenance of tissue stem cells of the intestine and the haematopoietic system. We therefore screened for genome stability factors negatively impacting maintenance of haematopoietic stem cells (HSC) in the context of ionising radiation (IR). We found that in vivo knock down of Xeroderma pigmentosum, complementation group G (Xpg) causes elevation of HSC numbers after IR treatment, while numbers of haematopoietic progenitors are elevated to a lesser extent. IR rapidly induces Xpg both on mRNA and on protein level. Prevention of this induction does not influence activation of the checkpoint cascade, yet attenuates late checkpoint steps such as induction of p21 and Noxa. This causes a leaky cell cycle arrest and lower levels of apoptosis, both contributing to increased colony formation and transformation rates. Xpg thus helps to adequately induce DNA damage responses after IR, thereby keeping the expansion of damaged cells under control. This represents a new function of Xpg in the response to IR, in addition to its well-characterized role in nucleotide excision repair.