Abstract
Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots.
Highlights
Recurring chromosome translocations are often associated with specific types of leukemia/cancer and DNA damaging agents[1]
To examine the involvement of ataxia-telangiectasia mutated (ATM) kinase and recombination proteins in 11q23 chromosomal translocations, we first analyzed the rearrangement of the MLL gene after etoposide treatment in ATM-deficient AT5BIVA cells and a clone of AT5BIVA complemented with chromosome 11 (11-4), which carries the ATM gene (Figure 1A)
Loading of RAD51 onto the breakpoint cluster region (BCR) after etoposide treatment is modulated by ATM Since increased levels of RAD51 promoted 11q23 chromosomal translocations after etoposide treatment, we examined whether etoposide treatment and/or ATM kinase activity affect RAD51 expression
Summary
Recurring chromosome translocations are often associated with specific types of leukemia/cancer and DNA damaging agents[1]. Breakpoints of these chromosome translocations have been shown to cluster within restricted regions in or around the genes implicated in the translocations. Among drugs used for anti-cancer chemotherapy, etoposide, a topoisomerase II inhibitor, has been clearly associated with the therapy-related leukemia carrying 11q23 chromosome translocations [4,5]. Most chromosomal translocation breakpoints in 11q23 are located within an 8.3-kb breakpoint cluster region (BCR) spanning from exon 7 to 13 of the MLL gene [6,7]. How etoposide induces 11q23 chromosome translocations in this region is largely unknown [8]
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