Cdt1 proteolysis is promoted by dual PIP degrons and is modulated by PCNA ubiquitylation.
Autor: Guarino Almeida, Estrella; Shepherd, Marianne E. A.; Salguero, Israel; Hua, Hui; Deegan, Rachel S.; Kearsey, Stephen E.
Resumen: Cdt1 plays a critical role in DNA replication regulation
by controlling licensing. In Metazoa, Cdt1 is
regulated by CRL4Cdt2-mediated ubiquitylation,
which is triggered by DNA binding of proliferating
cell nuclear antigen (PCNA). We show here that
fission yeast Cdt1 interacts with PCNA in vivo and
that DNA loading of PCNA is needed for Cdt1 proteolysis
after DNA damage and in S phase. Activation
of this pathway by ultraviolet (UV)-induced DNA
damage requires upstream involvement of nucleotide
excision repair or UVDE repair enzymes.
Unexpectedly, two non-canonical PCNA-interacting
peptide (PIP) motifs, which both have basic residues
downstream, function redundantly in Cdt1 proteolysis.
Finally, we show that poly-ubiquitylation
of PCNA, which occurs after DNA damage,
reduces Cdt1 proteolysis. This provides a mechanism
for fine-tuning the activity of the CRL4Cdt2
pathway towards Cdt1, allowing Cdt1 proteolysis
to be more efficient in S phase than after DNA
damage.
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