A breathtaking phenotype Unexpected roles of the DNA base damage response protein ASCIZ as a key regulator of early lung development
A breathtaking phenotype Unexpected roles of the DNA base damage response protein ASCIZ as a key regulator of early lung development
复制标题
DOI：
10.4161/cc.10.8.15336
复制
发表时间：
2011-04-15
期刊：
影响因子：
4.3
通讯作者：
Jurado, Sabine
中科院分区：
文献类型：
--
作者：
Heierhorst, Joerg;Smyth, Ian;Jurado, Sabine
ATM底物chk2相互作用的Zn2+手指蛋白（ASCIZ，也称为ATMIN和ZNF822）先前已被报道在甲基化和氧化DNA损伤的修复中起重要作用，并且还被提出调节ATM激酶的稳定性和DNA损伤无关的激活。虽然该蛋白在ATM调控中的作用仍有争议，但最近的两篇ASCIZ小鼠敲除论文证实了其在DNA碱基损伤反应中的作用，包括体内氧化应激抵抗。与其他DNA碱基损伤修复蛋白类似，ASCIZ对胚胎发育至关重要，无ASCIZ的胚胎在受孕后第16.5天左右死亡。出乎意料的是，ASCIZ的缺失也会导致严重的器官发育缺陷，最明显的是肺的完全缺失，类似于Wnt2-2b/ β -连环蛋白和FGF10/FGFR2b信号通路的突变体。结合证据表明ASCIZ可以在体外激活转录，该表型表明ASCIZ具有双重功能，既是DNA碱基损伤修复的效率因子，也是早期肺发育的关键转录调节因子。
T he ATM substrate Chk2-interacting Zn2+-finger protein (ASCIZ, also known as ATMIN and ZNF822) has previously been reported to be important for the repair of methylating and oxidative DNA damage, and it has also been proposed to regulate the stability and DNA damage-independent activation of the ATM kinase. While the role of the protein in the regulation of ATM remains controversial, two recent ASCIZ mouse knockout papers confirm its role in the DNA base damage response, including oxidative stress resistance in vivo. Similar to other DNA base damage repair proteins, ASCIZ is essential for embryonic development, with lethality of Asciz-null embryos around day E16.5 post conception. Unexpectedly, absence of ASCIZ also leads to severe organ development defects, most notably, complete absence of lungs similar to mutants in Wnt2-2b/beta-catenin and FGF10/FGFR2b signaling pathways. Together with evidence that ASCIZ can activate transcription in vitro, the phenotype indicates that ASCIZ has dual functions as an efficiency factor for DNA base damage repair as well as a key transcriptional regulator of early lung development.