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Cell cycle

Disposing of SETD8

Nature Reviews Molecular Cell Biology volume 11, page 819 (2010)Cite this article

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CRL4CDT2 regulates the cell cycle by degrading proteins that interfere with S phase progression. CRL4CDT2 substrates contain a proliferating cell nuclear antigen (PCNA)-interacting motif, which, together with another two sequence elements, is known as the PCNA-interacting peptide (PIP) degron. SETD8 contains a PIP degron, so it could be a CRL4CDT2 substrate. The three studies found that the SETD8 PIP degron was required for its interaction with PCNA, which has a role in promoting CRL4CDT2-mediated degradation, as SETD8 with a mutation in its PIP degron fails to associate with PCNA. Furthermore, the mutant SETD8 is stable during S phase and following DNA damage caused by ultraviolet (UV) radiation, indicating that the interaction with PCNA is required for SETD8 proteasomal degradation.

The three groups then used small interfering RNAs to deplete the CDT2 subunit of CRL4CDT2 to determine whether SETD8 is ubiquitylated by CRL4CDT2, and observed inhibition of SETD8 degradation. In vitro ubiquitylation assays by all three groups confirmed that SETD8 ubiquitylation depends on CRL4CDT2.

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ORIGINAL RESEARCH PAPERS

  1. Abbas, T. et al. CRL4Cdt2 regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. Mol. Cell 40, 9–21 (2010) Article

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  2. Centore, R. C. et al. CRL4Cdt2-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol. Cell 40, 22–33 (2010) Article

    Article  CAS  Google Scholar 

  3. Oda, H. et al. Regulation of the histone H4 monomethylase PR-Set7 by CRL4Cdt2-mediated PCNA-dependent degradation during DNA damage. Mol. Cell 27 Oct 2010 (doi:10.1016/j.molcel.2010.10.011)

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Authors
  1. Rachel David
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David, R. Disposing of SETD8. Nat Rev Mol Cell Biol 11, 819 (2010). https://doi.org/10.1038/nrm3020

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