Preservation of genomic integrity in mouse embryonic stem cells.
Preservation of genomic integrity in mouse embryonic stem cells.
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DOI：
10.1007/978-1-4419-7037-4_5
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发表时间：
2010
影响因子：
--
通讯作者：
Tichy ED
中科院分区：
文献类型：
--
作者：
Stambrook PJ;Tichy ED
胚胎干细胞和生殖细胞有可能形成一个完整的有机体。一个共同的要求是，两者都必须有非常强大的机制来维护其基因组的完整性。这一点尤其正确，因为体细胞在体内具有非常高的突变频率，接近10-4，这将导致不可接受的胎儿致死率和先天性缺陷。值得注意的是，在杂合的内源可选标记上监测到的突变事件中，70%到80%是由于有丝分裂重组而导致的杂合性丢失，这是一种影响报告基因和交叉部位之间的多个杂合性位点的机制。本章研究了小鼠胚胎干细胞保持其基因组完整性的三种机制。与同基因的小鼠胚胎成纤维细胞相比，第一种方法需要将染色体同源物之间的突变和重组抑制两个数量级，后者的突变频率与成人体细胞相似。第二种方法使小鼠ES细胞对环境挑战高度敏感，并从自我更新的群体中消除受损细胞。小鼠ES细胞缺乏G1期检查点，因此受到电离辐射等外源性损伤的细胞不会停滞在G1/S期检查点，而是进入S期，损伤的DNA在此阶段复制，损伤加剧，并促使细胞凋亡。第三种机制研究了小鼠胚胎干细胞如何修复双链DNA断裂。体细胞主要使用容易出错的非同源末端连接，从目的论的角度来看，这对ES细胞是不利的，因为它会促进突变的积累。当ES细胞被检测到双链DNA断裂修复的首选途径时，他们主要利用高保真的同源介导的修复途径，从而将修复过程中突变的发生降至最低。当小鼠ES细胞被诱导分化时，主要的修复途径从同源介导的修复转换为体细胞特有的非同源末端连接。
Embryonic stem (ES) cells and germ cells have the potential to give rise to an entire organism. A common requirement is that both must have very robust mechanisms to preserve the integrity of their genomes. This is particularly true since somatic cells have very high mutation frequencies approaching 10–4 in vivo that would lead to unacceptable levels of fetal lethality and congenital defects. Notably, between 70% and 80% of mutational events monitored at a heterozygous endogenous selectable marker were loss of heterozygosity due to mitotic recombination, a mechanism that affects multiple heterozygous loci between the reporter gene and the site of crossing over. This chapter examines three mechanisms by which mouse embryonic stem cells preserve their genomic integrity. The first entails suppression of mutation and recombination between chromosome homologues by two orders of magnitude when compared with isogenic mouse embryo fibroblasts which had a mutation frequency similar to that seen in adult somatic cells. The second renders mouse ES cells hypersensitive to environmental challenge and eliminates damaged cells from the self-renewing population. Mouse ES cells lack a G1 checkpoint so that cells damaged by exogenous insult such as ionizing radiation do not arrest at the G1/S phase checkpoint but progress into the S phase where the damaged DNA is replicated, the damage exacerbated and the cells driven to apoptosis. The third mechanism examines how mouse ES cells repair double strand DNA breaks. Somatic cells predominantly utilize error prone nonhomologous end joining which, from a teleological perspective, would be disadvantageous for ES cells since it would promote accumulation of mutations. When ES cells were tested for the preferred pathway of double strand DNA break repair, they predominantly utilized the high fidelity homology-mediated repair pathway, thereby minimizing the incurrence of mutations during the repair process. When mouse ES cells are induced to differentiate, the predominant repair pathway switches from homology-mediated repair to nonhomologous end joining that is characteristic of somatic cells.
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影响因子：
30.8
作者：
Luo, GB;Santoro, IM;Bradley, A
通讯作者：
Bradley, A
影响因子：
2.7
作者：
BRIGS, R;KING, TJ
通讯作者：
KING, TJ
影响因子：
--
作者：
Larson, Jon S.;Yin, Moying;Stringer, James R.
通讯作者：
Stringer, James R.
DOI：
10.1016/j.mrfmmm.2008.07.009
发表时间：
2008-10-14
影响因子：
2.3
作者：
Fischer, Jared M.;Stringer, James R.
通讯作者：
Stringer, James R.
DOI：
10.1016/s0074-7696(08)61042-6
发表时间：
1953-01-01
影响因子：
--
作者：
HAMMERLING, J
通讯作者：
HAMMERLING, J