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

Sang-Min Jang, Ya Zhang, Koichi Utani, Haiqing Fu, Christophe E. Redon, Anna B. Marks, Owen K. Smith, Catherine J. Redmond, Adrian M. Baris, Danielle A. Tulchinsky and Mirit I. Aladjem ()
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Sang-Min Jang: Center for Cancer Research, NCI, NIH
Ya Zhang: Center for Cancer Research, NCI, NIH
Koichi Utani: Center for Cancer Research, NCI, NIH
Haiqing Fu: Center for Cancer Research, NCI, NIH
Christophe E. Redon: Center for Cancer Research, NCI, NIH
Anna B. Marks: Center for Cancer Research, NCI, NIH
Owen K. Smith: Center for Cancer Research, NCI, NIH
Catherine J. Redmond: Center for Cancer Research, NCI, NIH
Adrian M. Baris: Center for Cancer Research, NCI, NIH
Danielle A. Tulchinsky: Center for Cancer Research, NCI, NIH
Mirit I. Aladjem: Center for Cancer Research, NCI, NIH

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05177-6

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