title: Regulation of DNA replication and chromosomal polyploidy by the MLL-WDR5-RBBP5 methyltransferases.
abstract: DNA replication licensing occurs on chromatin, but how the chromatin template is regulated for replication remains mostly unclear. Here, we have analyzed the requirement of histone methyltransferases for a specific type of replication: the DNA re-replication induced by the downregulation of either Geminin, an inhibitor of replication licensing protein CDT1, or the CRL4CDT2 ubiquitin E3 ligase. We found that siRNA-mediated reduction of essential components of the MLL-WDR5-RBBP5 methyltransferase complexes including WDR5 or RBBP5, which transfer methyl groups to histone H3 at K4 (H3K4), suppressed DNA re-replication and chromosomal polyploidy. Reduction of WDR5/RBBP5 also prevented the activation of H2AX checkpoint caused by re-replication, but not by ultraviolet or X-ray irradiation; and the components of MLL complexes co-localized with the origin recognition complex (ORC) and MCM2-7 replicative helicase complexes at replication origins to control the levels of methylated H3K4. Downregulation of WDR5 or RBBP5 reduced the methylated H3K4 and suppressed the recruitment of MCM2-7 complexes onto replication origins. Our studies indicate that the MLL complexes and H3K4 methylation are required for DNA replication but not for DNA damage repair.
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wu
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yin
authors.affiliation: Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Chia-Fang Lee
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA.
authors.forename: Ivailo S
authors.initials: IS
authors.lastname: Mihaylov
authors.affiliation: Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89154, USA.
authors.forename: Jiekai
authors.initials: J
authors.lastname: Yu
authors.affiliation: Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89154, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Basic Science Division, Nevada Cancer Institute, Las Vegas, NV 89135, USA Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, NV 89154, USA hui.zhang@unlv.edu.
authors.forename: Hui
authors.identifier: http://orcid.org/0000-0001-6028-2554
authors.initials: H
authors.lastname: Zhang
keywords: DNA replication; H3K4 methylation; RBBP5; Re-replication; WDR5