染色体転座形成と細胞核ダイナミクス

抄録

Chromosomal translocations are one of the most common types of genetic rearrangement induced by agents that damage DNA. Chromosomal translocations involving 11q23 are the most frequent chromosomal aberrations in secondary leukemia. The molecular mechanisms of chromosomal translocations, however, remain largely unknown. We found that a defect of ATM kinase, a DNA damage signaling regulator, increases the incidence of 11q23 chromosomal translocation in etoposide-treated cells. We also observed that the phosphorylation of ARP8, a subunit of the INO80 chromatin remodeling complex, after etoposide treatment is regulated by ATM and attenuates ARP8 interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of your INO80 and RAD51, a recombinase involved in DNA repair, onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8 regulated by ATM plays an important role in maintaining the accuracy of DNA repair to prevent etoposide-induced 11q23 abnormalities. We also examined the changes of higher-order nuclear structures around breakpoints of 11q23 translocations. Studies of mechanisms of chromosomal translocations will contribute to the prevention of late effects of cancer treatment in childhood.