- 武田 俊一 教授（京都大学医学研究科 放射線遺伝学）
- BRCA1, BRCA2, and PALB2 protect transcriptional response to estrogens from 'abortive' catalysis by Topoisomerase II
- DNA double-strand breaks (DSBs) are frequently formed by 'abortive' catalysis of Topoisomerase II (TOP2) during physiological cell cycle and in resting cells. Activated nuclear receptors induce rapid transcriptional responses by activating Topoisomerase IIbeta (TOP2b). TOP2 generates transient enzyme-bridged DSBs, TOP2 cleavage complexes (TOP2ccs). The abortive catalysis involves failed religation of the DSB by TOP2 leading to formation of pathological TOP2ccs, where TOP2 stably binds to 5’ DSB ends. Religation of pathological TOP2ccs requires removal of TOP2 adducts by MRE11 endonuclease followed by nonhomologous end joining (NHEJ). BRCA1, BRCA2, and PALB2 form a complex, and initiate homologous recombination (HR). We revealed that this complex promotes the removal of 5’ TOP2 adducts from DSBs independently of its role in HR in the G1 phase. BRCA1-BRCA2-PALB2 complex efficiently repairs DSBs induced by estrogens, which DSB formation results from activated estrogen receptors and subsequent abortive catalyses of TOP2b. Defective DSB repair causes accumulation of DSBs in enhancer sequences of the C-MYC oncogene leading to a few times increase in the induction of C-MYC transcription upon an exposure to estrogens. A defect in NHEJ also causes increases in both DSB formation and C-MYC induction in mammary epithelial cells upon the injection of estrogens into mice. We propose that the BRCA1-BRCA2-PALB2 complex prevents the oncogenesis of mammary epithelium by repairing estrogen-induced DSBs and preventing abnormal C-MYC response to estrogens.
細胞制御工学研究センターコロキウム 0047 ポスター