Repair of DNA double-strand break(DSB)is critical for the maintenance of genome integrity.A class of DSB-induced small RNAs(di RNAs)has been shown to play an important role in DSB repair.In humans,di RNAs are associat...Repair of DNA double-strand break(DSB)is critical for the maintenance of genome integrity.A class of DSB-induced small RNAs(di RNAs)has been shown to play an important role in DSB repair.In humans,di RNAs are associated with Ago2 and guide the recruitment of Rad51 to DSB sites to facilitate repair by homologous recombination(HR).Ago2 activity has been reported to be regulated by phosphorylation under normal and hypoxic conditions.However,the role of Ago2 phosphorylation in DNA damage repair is unexplored.Here,we show that S672,S828,T830,and S831 of human Ago2 are phosphorylated in response to ionizing radiation(IR).S672 A mutation of Ago2 leads to significant reduction in Rad51 foci formation and HR efficiency.We further show that defective association of Ago2 S672 A variant with DSB sites,instead of defects in di RNA and Rad51 binding,may account for decreased Rad51 foci formation and HR efficiency.Our study reveals a novel regulatory mechanism for the function of Ago2 in DNA repair.展开更多
基金supported by the National Natural Science Foundation of China(31401202)。
文摘Repair of DNA double-strand break(DSB)is critical for the maintenance of genome integrity.A class of DSB-induced small RNAs(di RNAs)has been shown to play an important role in DSB repair.In humans,di RNAs are associated with Ago2 and guide the recruitment of Rad51 to DSB sites to facilitate repair by homologous recombination(HR).Ago2 activity has been reported to be regulated by phosphorylation under normal and hypoxic conditions.However,the role of Ago2 phosphorylation in DNA damage repair is unexplored.Here,we show that S672,S828,T830,and S831 of human Ago2 are phosphorylated in response to ionizing radiation(IR).S672 A mutation of Ago2 leads to significant reduction in Rad51 foci formation and HR efficiency.We further show that defective association of Ago2 S672 A variant with DSB sites,instead of defects in di RNA and Rad51 binding,may account for decreased Rad51 foci formation and HR efficiency.Our study reveals a novel regulatory mechanism for the function of Ago2 in DNA repair.
