ATM modulates the loading of recombination proteins onto a chromosomal translocation breakpoint hotspot.
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.
Department of Cellular Biology, RIRBM, Hiroshima University, Hiroshima, Japan.
Jiying
J
Sun
Yukako
Y
Oma
Masahiko
M
Harata
Kazuteru
K
Kono
Hiroki
H
Shima
Aiko
A
Kinomura
Tsuyoshi
T
Ikura
Hidekazu
H
Suzuki
Shuki
S
Mizutani
Roland
R
Kanaar
Satoshi
S
Tashiro
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002880:Chromosomes, Human, Pair 11; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D051716:Replication Protein A / Q000378:metabolism; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D051716:Replication Protein A; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D011495:Histone-Lysine N-Methyltransferase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase