The role of PR-Set7 in replication licensing depends on Suv4-20h

• Published in: Genes & Development
• Main Authors: Beck, David B., Burton, Adam, Oda, Hisanobu, Ziegler-Birling, Céline, Torres-Padilla, Maria-Elena, Reinberg, Danny
• Format: Text
• Language: English
• Published: Cold Spring Harbor Laboratory Press 2012
• Subjects: Research Papers; Orca
• Online Access: http://genesdev.cshlp.org/cgi/content/short/gad.195636.112v1; https://doi.org/10.1101/gad.195636.112

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 CRL4Cdt2 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 CRL4Cdt2 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.