安井 明

I have been working in the research field of DNA repair. I began my research in Molecular Biology of DNA repair with the cloning of DNA repair genes in the yeast, Saccharomyces cerevisiae. It was the first cloning of DNA repair gene (actually two genes at once, photolyase and a nucleotide excision repair gene, Rad1) ever isolated from a eukaryotic organism (Yasui and Chevalier, Curr Genet. 1983). Soon after the cloning, I found similarity in the DNA repair proteins between prokaryote and eukaryote (Yasui and Langeveld, Gene 1985) and between yeast and human (van Duin et al., Cell 1986). These findings were the basis for the understanding of evolutionary conservation of DNA repair in life. I found also the diversity of DNA repair. While aplacental mammal (kangaroo) possesses light-dependent repair enzyme for UV damage (photolyase), placental mammal like us does not (Yasui et al. EMBO J. 1994). However, I found later that placental mammals and many of higher eukaryotes possess homologs of photolyase, which are required not for DNA repair but for circadian rhythms (van der Horst et al. Nature, 1999). As another example of the diversity of DNA repair, I found an excision repair for UV damage initiated by a single endonuclease, UV damage endonuclease, UVDE, which represents the alternative excision repair (Yajima et al. EMBO J. 1995, Yasui A. CSH Perspectives in Biol. 2013). This repair is single-strand break repair, in which activation of poly(ADP-ribose) polymerase (PARP) is required, if it is expressed in mammalian cell. We have shown how single-strand break repair proceeds in real time and live by using UVDE expressing human cell and laser micro-irradiation system, which we developed for analysis of DNA damage response and repair in living human cell (Okano et al. Mol Cell Biol. 2003, Lan et al. PNAS, 2004).
Real time laser micro-irradiation method was combined with proteome analysis (proteomics), we began to analyze the roles of chromatin remodeling in DNA damage response and repair. We have found for the first time that an ATP-dependent nucleosome remodeling complex ACF/CHRAC belonging to ISWI family interacts with KU in response to Bleomycin-treatment of cells, recruits NHEJ repair at DSB site and contribute to cellular resistance to DSB (Lan et al. Mol Cell 2010). The method of visualized analysis of proteins combined with proteomics was used to identify proteins required for the repair of DSB and other types of DNA damage (Kanno et al. EMBO J. 2007, Ito et al. EMBO J. 2011, Xue et al. Nature Genet. 2012, Watanabe et al. Cancer Res. 2014). Transcription-coupled DNA repair has been known for UV-induced DNA damage, but we found that in case of DSB, ATM activated by DSB phosphorylates a factor ENL promoting transcriptional elongation in RNA PolII complex, which recruits Polycomb complex PRC1 by direct interaction with BMI1 and ubiquitinates histone H2A to suppress on going transcription (Ui et al. Mol Cell).
Based on the paper (Watanabe et al. Cancer Res. 2014), I have proposed a new cell aging model; Age-dependent decline of nucleosome remodeling causes negative feedback loops among DNA repair, nucleosome remodeling and transcriptional regulation leading to accelerated cellular aging (Watanabe et al. in press). I’m concentrating on the model.