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XB-ART-54198
Mol Cell 2017 Oct 19;682:350-360.e7. doi: 10.1016/j.molcel.2017.09.037.
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Structure of the Dnmt1 Reader Module Complexed with a Unique Two-Mono-Ubiquitin Mark on Histone H3 Reveals the Basis for DNA Methylation Maintenance.

Ishiyama S , Nishiyama A , Saeki Y , Moritsugu K , Morimoto D , Yamaguchi L , Arai N , Matsumura R , Kawakami T , Mishima Y , Hojo H , Shimamura S , Ishikawa F , Tajima S , Tanaka K , Ariyoshi M , Shirakawa M , Ikeguchi M , Kidera A , Suetake I , Arita K , Nakanishi M .


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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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Species referenced: Xenopus laevis
Genes referenced: cdt1 dnmt1 krt18.1 pcna uhrf1
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