The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin

• Published in: Nature communications Vol. 9; no. 1; pp. 2782 - 13
• Main Authors: Jang, Sang-Min, Zhang, Ya, Utani, Koichi, Fu, Haiqing, Redon, Christophe E., Marks, Anna B., Smith, Owen K., Redmond, Catherine J., Baris, Adrian M., Tulchinsky, Danielle A., Aladjem, Mirit I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 14/1; 14/19; 45/15; 45/22; 45/23; 631/337/151; 631/337/151/2355; 631/337/458/582; 631/337/475/2290; 631/67/1059; 82/29; 82/80; 82/83; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Chromatin; Chromatin - chemistry; Chromatin - metabolism; Chromosomes; Cullin Proteins - genetics; Cullin Proteins - metabolism; Cyclopentanes - pharmacology; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Replication; Eukaryotes; Gene Expression; Genomes; HCT116 Cells; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; K562 Cells; multidisciplinary; Origins; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Protein Binding; Protein Transport; Proteins; Pyrimidines - pharmacology; Replication; Replication initiation; Replication Origin; Replication origins; S-Phase Kinase-Associated Proteins - antagonists & inhibitors; S-Phase Kinase-Associated Proteins - genetics; S-Phase Kinase-Associated Proteins - metabolism; Science; Science (multidisciplinary); Skp2 protein; Stem Cell Factor - genetics; Stem Cell Factor - metabolism; Substrates; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05177-6

Cell cycle progression in mammals is modulated by two ubiquitin ligase complexes, CRL4 and SCF, which facilitate degradation of chromatin substrates involved in the regulation of DNA replication. One member of the CRL4 complex, the WD-40 containing protein RepID (DCAF14/PHIP), selectively binds and activates a group of replication origins. Here we show that RepID recruits the CRL4 complex to chromatin prior to DNA synthesis, thus playing a crucial architectural role in the proper licensing of chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase, SKP2-containing SCF, to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, which triggered massive genome re-replication. Both RepID and SKP2 interact with distinct, non-overlapping groups of replication origins, suggesting that selective interactions of replication origins with specific CRL components execute the DNA replication program and maintain genomic stability by preventing re-initiation of DNA replication. RepID has previously been shown to promote origin firing. Here the authors reveal that RepID regulates replication origins via the recruitment of the CRL4 complex, and prevents re-initiation and unscheduled DNA replication.