Regulation of maintenance DNA methylation by histone ubiquitylation
Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. Although it is well established that Uhrf1 specifically binds to hemi-methylated DNA through its SRA domain and plays an essential role in maintenance of DNA methylation by recruiting Dnmt1 to hemi-methylated DNA sites, the mechanism of how Uhrf1 coordinates the maintenance of DNA methylation and DNA replication is largely unknown. We demonstrate here that Uhrf1-dependent histone H3 ubiquitylation plays a prerequisite role in the maintenance DNA methylation. Using Xenopus egg extracts, we successfully reproduced maintenance DNA methylation in vitro. Dnmt1 depletion resulted in a dramatic accumulation of Uhrf1-dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associated with ubiquitylated H3 in vitro though a region previously identified as a replication foci targeting sequence. The RING finger mutant of Uhrf1 failed to recruit Dnmt1 to DNA replication sites and maintain DNA methylation in mammalian cultured cells. Our findings are thus the first evidence of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.
Prof. Makoto Nakanishi je diplomirao na Nagoya City University, Graduate School, Division of Medicine. Poslije boravka na Baylor College of Medicine u Houstonu, SAD istraživački rad je nastavio na Department of Cell Biology na Nagoya City University kojega je ujedno i voditelj od 2000. godine. Glavni pravci njegovih istraživanja su kontrola staničnog ciklusa, regulacija apoptoze od strane NF-κB i u posljednje vrijeme regulacija metilacije DNA ubikvitinacijom histona. Ova istraživanja je nedavno objavio u Nature što je ujedno i tema njegovog predavanja. Prof. Nakanishi je objavio više od 100 znanstvenih radova u prestižnim svjetskim časopisima koji uključuju pored Nature i Science, Cell, PNAS, EMBO journal itd.