ATR suppresses endogenous DNA damage and allows completion of homologous recombination repair.
ATR suppresses endogenous DNA damage and allows completion of homologous recombination repair.
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DOI：
10.1371/journal.pone.0091222
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Bishop AJ
中科院分区：
文献类型：
--
作者：
Brown AD;Sager BW;Gorthi A;Tonapi SS;Brown EJ;Bishop AJ
内源性损伤引起的DNA复制分叉停滞或崩溃对基因组的稳定性构成了严重的威胁，但细胞激活了一个复杂的信号级联，称为DNA损伤响应(DDR)来防止这种损伤。基因产物共济失调、毛细血管扩张和RAD3相关(ATR)主要通过调节细胞周期检查点控制来响应复制应激，但它在DNA修复，特别是同源重组(HR)中的作用尚不清楚。这一点特别有意义，因为HR是在出现停滞或崩溃的分叉时进行复制重启的一种方式。人类ATR亚型突变导致罕见的常染色体隐性遗传病Seckel综合征，而小鼠ATR完全缺失会导致胚胎死亡。我们最近采用了体内小鼠粉眼不稳定(PUN)实验来测量HR频率，以便能够使用条件Cre/loxP系统来研究必要基因在HR中的作用。我们的系统为测试生理条件下ATR缺失对体细胞心率的影响提供了独特的机会。利用这一系统，我们提供了缺乏ATR的视网膜色素上皮(RPE)细胞密度降低、形态异常、心率降低和染色体损伤程度增加的证据。
DNA replication fork stalling or collapse that arises from endogenous damage poses a serious threat to genome stability, but cells invoke an intricate signaling cascade referred to as the DNA damage response (DDR) to prevent such damage. The gene product ataxia telangiectasia and Rad3-related (ATR) responds primarily to replication stress by regulating cell cycle checkpoint control, yet it’s role in DNA repair, particularly homologous recombination (HR), remains unclear. This is of particular interest since HR is one way in which replication restart can occur in the presence of a stalled or collapsed fork. Hypomorphic mutations in human ATR cause the rare autosomal-recessive disease Seckel syndrome, and complete loss of Atr in mice leads to embryonic lethality. We recently adapted the in vivo murine pink-eyed unstable (pun) assay for measuring HR frequency to be able to investigate the role of essential genes on HR using a conditional Cre/loxP system. Our system allows for the unique opportunity to test the effect of ATR loss on HR in somatic cells under physiological conditions. Using this system, we provide evidence that retinal pigment epithelium (RPE) cells lacking ATR have decreased density with abnormal morphology, a decreased frequency of HR and an increased level of chromosomal damage.
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DOI：
10.1083/jcb.200402095
发表时间：
2004-06-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li W;Kim SM;Lee J;Dunphy WG
通讯作者：
Dunphy WG
影响因子：
11.2
作者：
McCabe, Nuala;Turner, Nicholas C.;Ashworth, Alan
通讯作者：
Ashworth, Alan
影响因子：
4.7
作者：
Bishop, AJR;Kosaras, B;Schiestl, RH
通讯作者：
Schiestl, RH
影响因子：
64.8
作者：
Lopes, M;Cotta-Ramusino, C;Foiani, M
通讯作者：
Foiani, M
影响因子：
4.8
作者：
Gunn, Amanda;Bennardo, Nicole;Stark, Jeremy M.
通讯作者：
Stark, Jeremy M.