CUL4B keeps replication firing on all cylinders

Zou et al. describe how a protein linked to mental retardation promotes DNA replication.

Mutations in CUL4B, a member of the cullin family of ubiquitin ligase scaffold proteins, are associated with mental retardation and other developmental defects. Human cells lacking CUL4B progress slowly through S phase, though how DNA replication is impaired in these cells is unknown.

Zou et al. found that depleting CUL4B decreased the ability of replication origins to “fire” and initiate DNA synthesis. Cells lacking CUL4B had reduced amounts of nuclear CDC6, a protein that licenses DNA replication by promoting the assembly of prereplication complexes at origin sites. Overexpressing CDC6 restored origin firing to normal rates.

CDC6 levels were lowered in CUL4B-deficient cells by the ubiquitin ligase APC^CDH1. The cyclin-dependent kinase CDK2 can phosphorylate and protect CDC6 from APC^CDH1-mediated degradation, but CDK2 expression was reduced in the absence of CUL4B, increasing CDC6’s turnover. Zou et al. found that CUL4B up-regulates CDK2 by inhibiting the production of two microRNAs, miR-372 and miR-373, that target the kinase. In CUL4B’s absence, the two microRNAs were up-regulated, leading to a decrease in CDC6 levels and replication origin firing.

How CUL4B represses miR-372 and miR-373 remains unclear. Because CUL4B-containing ubiquitin ligases interact with the histone-modifying complex PRC2, the authors speculate that the microRNAs may be regulated by histone methylation.