Double-strand DNA break repair: molecular mechanisms and therapeutic targets

The MRN complex is the initiation complex in theHR repair pathway. MRN complexes are rapidly recruited
to DSB sites, where they initiate DSB end resectionsand maintain DSB ends in preparation for subsequent
repair. In addition, ATM is recruited and activated tocoordinate DSB repair and cell cycle progression.42–44
ATM kinase activity in cells is initiated by intermolecular autophosphorylation at S1981, S367, and S1893.43 Theautophosphorylation of ATM enables it to dissociate intoactive monomer and be reactivated, enabling ATM toremain at DNA damage sites, where it catalyzes necessarydownstream phosphorylation events.41,43,45 When ATMis activated at DSBs, histone H2AX is phosphorylated toproduce H2AX, which then attracts and phosphorylatesMDC1 and activates two E3 ubiquitin ligases, RNF8 andRNF168, to start a ubiquitination (UB) cascade.2 Chromatin conformation changes caused by a series of signaling cascades promote the recruitment of multiple factors,including BRCA1, CtIP (MRX and Sae2 in yeast), EXO1,and BLM.46 The MRN complex and CtIP form complexeswith BRCA1, which is essential for facilitating DSB endresection.47,4
感谢中国湖南省衡阳市华南大学衡阳医学院；北京放射医学研究所北京放射生物学重点实验室辐射生物学系（中国北京）*通讯作者：高珊珊，北京放射医学研究所北京放射生物学重点实验室辐射生物学系，引用文献