TY - JOUR TI - Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations AU - Sun, Jiying AU - Shi, Lin AU - Kinomura, Aiko AU - Fukuto, Atsuhiko AU - Horikoshi, Yasunori AU - Oma, Yukako AU - Harata, Masahiko AU - Ikura, Masae AU - Ikura, Tsuyoshi AU - Kanaar, Roland AU - Tashiro, Satoshi A2 - Workman, Jerry L VL - 7 PY - 2018 DA - 2018/05/08 SP - e32222 C1 - eLife 2018;7:e32222 DO - 10.7554/eLife.32222 UR - https://doi.org/10.7554/eLife.32222 AB - Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment. The etoposide-induced phosphorylation of ARP8 is regulated by ATM and ATR, and attenuates its interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of INO80 and RAD51 onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8, regulated by ATM, plays an important role in maintaining the fidelity of DNA repair to prevent the etoposide-induced 11q23 abnormalities. KW - ATM KW - ARP8 phosphorylation KW - chromosome translocations KW - INO80 KW - RAD51 KW - ATR JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -