当前位置: X-MOL 学术Mol. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
DNA-PKcs chemical inhibition versus genetic mutation: Impact on the junctional repair steps of V(D)J recombination.
Molecular Immunology ( IF 3.2 ) Pub Date : 2020-02-26 , DOI: 10.1016/j.molimm.2020.01.018
Z Anne Esguerra 1 , Go Watanabe 1 , Cindy Y Okitsu 2 , Chih-Lin Hsieh 2 , Michael R Lieber 1
Affiliation  

Spontaneous DNA-PKcs deficiencies in animals result in a severe combined immunodeficiency (SCID) phenotype because DNA-PKcs is required to activate Artemis for V(D)J recombination coding end hairpin opening. The impact on signal joint formation in these spontaneous mutant mammals is variable. Genetically engineered DNA-PKcs null mice and cells from them show a >1,000-fold reduction in coding joint formation and minimal reduction in signal joint formation during V(D)J recombination. Does chemical inhibition of DNA-PKcs mimic this phenotype? M3814 (also known as Nedisertib) is a potent DNA-PKcs inhibitor. We find here that M3814 causes a quantitative reduction in coding joint formation relative to signal joint formation. The sequences of signal and coding junctions were within normal limits, though rare coding joints showed novel features. The signal junctions generally did not show evidence of resection into the signal ends that is often seen in cells that have genetic defects in DNA-PKcs. Comparison of the chemical inhibition findings here with the known results for spontaneous and engineered DNA-PKcs mutant mammals is informative for considering pharmacologic small molecule inhibition of DNA-PKcs in various types of neoplasia.

中文翻译:

DNA-PKcs化学抑制与遗传突变:对V(D)J重组的结合修复步骤的影响。

动物中自发性DNA-PKcs缺陷会导致严重的联合免疫缺陷(SCID)表型,因为需要DNA-PKcs才能激活Artemis进行V(D)J重组编码末端发夹的打开。在这些自发突变哺乳动物中对信号关节形成的影响是可变的。基因工程改造的DNA-PKcs空小鼠和它们的细胞在V(D)J重组过程中显示出编码关节形成的减少> 1,000倍,并且信号关节形成的减少最小。DNA-PKcs的化学抑制是否模仿该表型?M3814(也称为Nedisertib)是一种有效的DNA-PKcs抑制剂。我们在这里发现,相对于信号接头的形成,M3814导致编码接头的形成定量减少。信号和编码接头的序列在正常范围内,尽管罕见的编码接头显示出新颖的特征。信号连接通常没有显示出切除信号末端的证据,而DNA-PKcs中存在遗传缺陷的细胞中经常见到信号切除。自发的和工程化的DNA-PKcs突变哺乳动物的化学抑制结果与已知结果的比较,对于考虑在各种类型的肿瘤中对DNA-PKcs的药理学小分子抑制是有益的。
更新日期:2020-02-26
down
wechat
bug