Copy number variants are produced in response to low-dose ionizing radiation in cultured cells.
Copy number variants are produced in response to low-dose ionizing radiation in cultured cells.
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DOI：
10.1002/em.21840
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发表时间：
2014-03
影响因子：
2.8
通讯作者：
Glover, Thomas W.
中科院分区：
文献类型：
--
作者：
Arlt, Martin F.;Rajendran, Sountharia;Birkeland, Shanda R.;Wilson, Thomas E.;Glover, Thomas W.
尽管它们对人类遗传变异和疾病的重要性，但对影响拷贝数变异（CNV）形成的分子机制和环境风险因素知之甚少。虽然复制应激可以导致新生CNV是清楚的，例如在用阿非迪霉素（APH）和羟基脲（HU）处理培养的哺乳动物细胞之后，不同类型的诱变剂对CNV诱导的影响是未知的。在这里，我们报告，电离辐射（IR）在1.5-3.0戈伊的范围内有效地诱导新生CNV突变培养的正常人成纤维细胞。这些IR诱导的CNV在整个基因组中发现，在APH和HU诱导的复制应激后观察到相同的热点区域。相对于缺失，IR产生重复的频率高于APH和HU。在大多数热点，这些重复是从通常在APH或HU后删除的区域物理转移的，这表明它们的形成涉及不同的途径。来自辐照样品的CNV断点连接的特征在于微同源性、平端和插入，如在体内自发和APH/HU诱导的CNV和大多数非复发性CNV中所见。与APH/HU诱导的CNVs的相似性表明，低剂量IR通过复制依赖性机制诱导CNVs，而不是复制独立的DSB修复。与该机制一致，当细胞在照射后重新铺板之前保持48小时时，观察到较低的CNV产率。这些结果预测，任何损害复制的环境DNA损伤剂都能够产生CNVs。
Despite their importance to human genetic variation and disease, little is known about the molecular mechanisms and environmental risk factors that impact copy number variant (CNV) formation. While it is clear that replication stress can lead to de novo CNVs, for example following treatment of cultured mammalian cells with aphidicolin (APH) and hydroxyurea (HU), the effect of different types of mutagens on CNV induction is unknown. Here we report that ionizing radiation (IR) in the range of 1.5–3.0 Gy effectively induces de novo CNV mutations in cultured normal human fibroblasts. These IR-induced CNVs are found throughout the genome, with the same hotspot regions seen after APH- and HU-induced replication stress. IR produces duplications at a higher frequency relative to deletions than do APH and HU. At most hotspots, these duplications are physically shifted from the regions typically deleted after APH or HU, suggesting different pathways involved in their formation. CNV breakpoint junctions from irradiated samples are characterized by microhomology, blunt ends, and insertions like those seen in spontaneous and APH/HU-induced CNVs and most nonrecurrent CNVs in vivo. The similarity to APH/HU-induced CNVs suggests that low-dose IR induces CNVs through a replication-dependent mechanism, as opposed to replication-independent repair of DSBs. Consistent with this mechanism, a lower yield of CNVs was observed when cells were held for 48h before re-plating after irradiation. These results predict that any environmental DNA damaging agent that impairs replication is capable of creating CNVs.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.131009198
发表时间：
2001-07-17
影响因子：
11.1
作者：
Kuzminov, A
通讯作者：
Kuzminov, A
影响因子：
11
作者：
Huang HL;Hsing HW;Lai TC;Chen YW;Lee TR;Chan HT;Lyu PC;Wu CL;Lu YC;Lin ST;Lin CW;Lai CH;Chang HT;Chou HC;Chan HL
通讯作者：
Chan HL
影响因子：
3.8
作者：
Harper, Jane V.;Anderson, Jennifer A.;O'Neill, Peter
通讯作者：
O'Neill, Peter
影响因子：
9.8
作者：
Arlt, Martin F.;Mulle, Jennifer G.;Glover, Thomas W.
通讯作者：
Glover, Thomas W.