B-Myb is critical for proper DNA duplication during an unperturbed S phase in mouse embryonic stem cells.
B-Myb is critical for proper DNA duplication during an unperturbed S phase in mouse embryonic stem cells.
复制标题
DOI：
10.1002/stem.496
复制
发表时间：
2010-10
期刊：
影响因子：
5.2
通讯作者：
Garcia, Paloma
中科院分区：
文献类型：
--
作者：
Lorvellec, Maelle;Dumon, Stephanie;Maya-Mendoza, Apolinar;Jackson, Dean;Frampton, Jon;Garcia, Paloma
关键词：
来自内细胞团（ICM）的早期胚胎细胞和ESC的共同特征是绝对依赖于非典型细胞周期，其中G1期缩短以保持其自我更新和多能性。转录因子B-Myb被认为在增殖中起作用，特别是在细胞周期的G2/M期。有趣的是，ICM/ESCs中的B-Myb水平是正常增殖细胞中的100倍以上，这表明这种转录因子在多能干细胞中具有特别重要的功能。B-Myb对胚胎发育至关重要，但其在ICM/ESCs中的作用尚不清楚。使用小鼠遗传学，单DNA纤维分析和高分辨率三维（3D）成像的组合，我们证明，B-Myb对多能性因子的表达没有影响，而是B-Myb消融导致复制叉的停滞和复制工厂的超激活，导致复制程序的混乱和双链断裂的增加。这些影响部分是由于细胞周期增殖因子，即c-Myc和FoxM 1，这决定了正常的S期进展的异常转录调控。我们的结论是，B-Myb的行为至关重要，在S期在胚胎干细胞通过促进适当的复制进展，从而保护细胞免受基因组损伤。我们的研究结果具有特别的意义，鉴于潜在的治疗应用的胚胎干细胞和需要保持其基因组的完整性。
A common feature of early embryo cells from the inner cell mass (ICM) and of ESCs is an absolute dependence on an atypical cell cycle in which the G1 phase is shortened to preserve their self-renewing and pluripotent nature. The transcription factor B-Myb has been attributed a role in proliferation, in particular during the G2/M phases of the cell cycle. Intriguingly, B-Myb levels in ICM/ESCs are greater than 100 times compared with those in normal proliferating cells, suggesting a particularly important function for this transcription factor in pluripotent stem cells. B-Myb is essential for embryo development beyond the preimplantation stage, but its role in ICM/ESCs remains unclear. Using a combination of mouse genetics, single DNA fiber analyses and high-resolution three-dimensional (3D) imaging, we demonstrate that B-Myb has no influence on the expression of pluripotency factors, but instead B-Myb ablation leads to stalling of replication forks and superactivation of replication factories that result in disorganization of the replication program and an increase in double-strand breaks. These effects are partly due to aberrant transcriptional regulation of cell cycle proliferation factors, namely c-Myc and FoxM1, which dictate normal S phase progression. We conclude that B-Myb acts crucially during the S phase in ESCs by facilitating proper progression of replication, thereby protecting the cells from genomic damage. Our findings have particular relevance in the light of the potential therapeutic application of ESCs and the need to maintain their genomic integrity.
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DOI：
10.1083/jcb.139.7.1597
发表时间：
1997-12-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ferreira J;Paolella G;Ramos C;Lamond AI
通讯作者：
Lamond AI
影响因子：
4
作者：
García, P;Frampton, J
通讯作者：
Frampton, J
影响因子：
8
作者：
Knight, A. S.;Notaridou, M.;Watson, R. J.
通讯作者：
Watson, R. J.
影响因子：
64.8
作者：
Dominguez-Sola, David;Ying, Carol Y.;Dalla-Favera, Riccardo
通讯作者：
Dalla-Favera, Riccardo
影响因子：
9.2
作者：
Korver, W;Schilham, MW;Clevers, H
通讯作者：
Clevers, H