Structure of the Dnmt1 Reader Module Complexed with a Unique Two-Mono-Ubiquitin Mark on Histone H3 Reveals the Basis for DNA Methylation Maintenance
2017
Ishiyama, Satoshi | Nishiyama, Atsuya | Saeki, Yasushi | Moritsugu, Kei | Morimoto, Daichi | Yamaguchi, Luna | Arai, Naoko | Matsumura, Rumie | Kawakami, Toru | Mishima, Yuichi | Hojo, Hironobu | Shimamura, Shintaro | Ishikawa, Fuyuki | Tajima, Shoji | Tanaka, Keiji | Ariyoshi, Mariko | Shirakawa, Masahiro | Ikeguchi, Mitsunori | Kidera, Akinori | Suetake, Isao | Arita, Kyohei | Nakanishi, Makoto
The proper location and timing of Dnmt1 activation are essential for DNA methylation maintenance. We demonstrate here that Dnmt1 utilizes two-mono-ubiquitylated histone H3 as a unique ubiquitin mark for its recruitment to and activation at DNA methylation sites. The crystal structure of the replication foci targeting sequence (RFTS) of Dnmt1 in complex with H3-K18Ub/23Ub reveals striking differences to the known ubiquitin-recognition structures. The two ubiquitins are simultaneously bound to the RFTS with a combination of canonical hydrophobic and atypical hydrophilic interactions. The C-lobe of RFTS, together with the K23Ub surface, also recognizes the N-terminal tail of H3. The binding of H3-K18Ub/23Ub results in spatial rearrangement of two lobes in the RFTS, suggesting the opening of its active site. Actually, incubation of Dnmt1 with H3-K18Ub/23Ub increases its catalytic activity in vitro. Our results therefore shed light on the essential role of a unique ubiquitin-binding module in DNA methylation maintenance.
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