Abstract
p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.
Highlights
Abstract: p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs)
While the mechanisms of p53 induction by nutlin-3 and γ irradiation are dissimilar, both treatments converge into the accumulation of a transcriptionally active p53 that can promote p21 accumulation. Under this circumstance, live-cell imaging revealed that p21 accumulated in G1 was downregulated in the S phase, and accumulated rapidly again at the S/G2 transition [16]. Such modulation in p21 levels was intimately associated with the interaction of p21 with proliferating cell nuclear antigen (PCNA), as disruption of such interaction through a mutation of the p21 PCNA-interacting protein (PIP) box caused the accumulation of p21 in γ-irradiated cells transiting the S phase [67]
These results indicate that excess of exogenous p21 downregulation or the disruption of the PIP box of p21 allowed p21 upregulation in the S phase, indicating CRL4Cdt2 that degrades PCNA-bound p21, tightly controlling p21 levels in the S phase [16,67]
Summary
With its C terminus, p21 interacts with the proliferating cell nuclear antigen (PCNA), a protein that was discovered in 1978 and was initially described as an essential factor for proliferation [20]. Such modulation in p21 levels was intimately associated with the interaction of p21 with PCNA, as disruption of such interaction through a mutation of the p21 PIP box caused the accumulation of p21 in γ-irradiated cells transiting the S phase [67] Both studies concluded that the downregulation of p21 in the S phase was dependent on the CRL4cdt accumulated rapidly again at the S/G2 transition [16]. G1 after γ-irradiation [67], suggestinginteraction that p21–PCNA replicativeM147A, DNA and polymerases is needed to interaction prevented rather than promoted cell-cycle arrest, as originally postulated based on its prevent chromosome fusions and micronuclei that accumulate in cells expressing the p21 mutant ability to displace replicative DNA polymerases from PCNA [43,44].
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