Mechanism of genotoxicity involving DNA–protein cross-links

<p>We have investigated the mechanisms of genotoxicity involving proteins trapped at the ends of DNA. We found that the reduced repair efficiency of this type of DNA damage has a pivotal role in some diseases, such as breast cancer. At this symposium, we will present the induction of genotoxicity involving topoisomerases. Women having BRCA1 germ-line mutations develop cancer in breast and ovary, estrogen-regulated tissues, with high penetrance. Binding of estrogens to the estrogen receptor (ER) transiently induces DNA double-strand breaks (DSBs) by topoisomerase 2 (TOP2) and controls gene transcription. TOP2 resolves catenated DNA by transiently generating DSBs, TOP2-cleavage complexes (TOP2ccs), where TOP2 covalently binds to 5′ ends of DSBs. TOP2 frequently fails to complete its catalysis, leading to trapping TOP2ccs. We found that BRCA1 promotes the removal of trapped TOP2cc. BRCA1 thus plays a critical role in removing pathological TOP2ccs induced by estrogens. We propose that BRCA1 suppresses tumorigenesis by removing estrogen-induced TOP2ccs throughout the cell cycle. Furthermore, we focused on TOP1cc removal mechanism and found that TOP1cc is repaired via a two-step pathway involving proteasomal degradation of TOP1cc to the crosslinked peptide, followed by removal of the TOP1cc-derived peptide from DNA by tyrosyl-DNA phosphodiesterase 1 (TDP1). Our recent observations on the genotoxicity related to trapped topoisomerase will be discussed.</p>