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.