title: The role of PR-Set7 in replication licensing depends on Suv4-20h.
abstract: PR-Set7 is the sole monomethyltransferase responsible for H4K20 monomethylation (H4K20me1) that is the substrate for further methylation by Suv4-20h1/h2. PR-Set7 is required for proper cell cycle progression and is subject to degradation by the CRL4(Cdt2) ubiquitin ligase complex as a function of the cell cycle and DNA damage. This report demonstrates that PR-Set7 is an important downstream effector of CRL4(Cdt2) function during origin of DNA replication licensing, dependent on Suv4-20h1/2 activity. Aberrant rereplication correlates with decreased levels of H4K20me1 and increased levels of H4K20 trimethylation (H4K20me3). Expression of a degradation-resistant PR-Set7 mutant in the mouse embryo that is normally devoid of Suv4-20 does not compromise development or cell cycle progression unless Suv4-20h is coexpressed. PR-Set7 targeting to an artificial locus results in recruitment of the origin recognition complex (ORC) in a manner dependent on Suv4-20h and H4K20me3. Consistent with this, H4K20 methylation status plays a direct role in recruiting ORC through the binding properties of ORC1 and ORCA/LRWD1. Thus, coordinating the status of H4K20 methylation is pivotal for the proper selection of DNA replication origins in higher eukaryotes.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Beck
authors.forename: Adam
authors.initials: A
authors.lastname: Burton
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Oda
authors.forename: Céline
authors.initials: C
authors.lastname: Ziegler-Birling
authors.forename: Maria-Elena
authors.initials: ME
authors.lastname: Torres-Padilla
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051738:Origin Recognition Complex / Q000378:metabolism; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D051738:Origin Recognition Complex; C570043:Suv4-20h protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D044767:Ubiquitin-Protein Ligases