CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

  title={CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication},
  author={Sabrina Florencia Mansilla and Mar{\'i}a Bel{\'e}n de la Vega and Nicol{\'a}s Luis Calzetta and Sebasti{\'a}n Omar Siri and Vanesa Gottifredi},
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… Expand
Multiple biochemical properties of the p53 molecule contribute to activation of polymerase iota-dependent DNA damage tolerance
The mutational analysis demonstrates that transcriptional transactivation is dispensable for the POLι-mediated DDT pathway, which protects against DNA replication damage from endogenous and exogenous sources. Expand
p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway.
Mimicking the situation found to be associated with many cancer types and stem cells, i.e., co-expression of alternative p53-isoforms with p53α, carved out interference with p 53α functions in the p53/POLι-dependent DDT pathway. Expand
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Evidence is provided for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs. Expand
p21 can be a barrier to ferroptosis independent of p53
The data indicate that the interaction of p21 with CDKs is crucial for its ability to restrict the progression of ferroptosis, and the potential of p 21 to aid in maintenance of healthy tissues by blocking the damage incurred due to ferroPTosis. Expand
The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1
The new progress of the studies on Cyclin dependent kinase 20 and p21Cip1/Waf1 in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms are summarized. Expand
Cdt1 inhibits CMG helicase in early S phase to separate origin licensing from DNA synthesis
Cdt1 inhibits DNA synthesis during an overlap period when cells fire origins while Cdt1 is still present, and DNA synthesis commences once Cdt 1 is degraded. Expand
RNA-Binding Motif Protein 38 as a Potential Biomarker and Therapeutic Target in Cancer
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STAT3-mediated activation of mitochondrial pathway contributes to antitumor effect of dihydrotanshinone I in esophageal squamous cell carcinoma cells
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  • Medicine
  • World journal of gastrointestinal oncology
  • 2021
DHTS exerts antitumor effect in ESCC via STAT3-mediated activation of the mitochondrial pathway and may be a novel therapeutic agent for ESCC. Expand
LncRNA ENSG00000254615 Modulates Proliferation and 5-FU Resistance by Regulating p21 and Cyclin D1 in Colorectal Cancer
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CCNG1 oncogene: a novel biomarker for cancer therapy /gene therapy
Background: Metastatic cancer is associated with an invariably fatal outcome. However, DeltaRex-G, a tumor-targeted retrovector encoding a gene-edited dominant-negative CCNG1 inhibitor gene, hasExpand


Decreased p21 Levels Are Required for Efficient Restart of DNA Synthesis after S Phase Block*
It is shown here that during S phase arrest proteasome-mediated turnover of p21 is significantly increased in a manner that is independent of p53, implying that p21 down-regulation could be an essential requirement for efficient restart of DNA synthesis. Expand
Cell-cycle inhibition by independent CDK and PCNA binding domains in p21Cip1
When separately overexpressed in mammalian cells, the CDK and PCNA inhibitory domains prevent DNA replication, demonstrating a dual function of p21 as a cell-cycle inhibitor in vivo. Expand
Cyclin Kinase-independent role of p21CDKN1A in the promotion of nascent DNA elongation in unstressed cells
It is shown here that endogenous p21, instead of being residual, it is functional and necessary to preserve the genomic stability of unstressed cells and prevents a type of genomic instability which is not triggered by endogenous DNA lesions but by a dysregulation in the DNA polymerase choice during genomic DNA synthesis. Expand
p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells
A unique feature of p21 that distinguishes it from the other cyclin-dependent kinase (CDK) inhibitors is its ability to associate with the proliferating cell nuclear antigen (PCNA), an auxiliaryExpand
The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA
It is shown that p21 directly inhibits PCNA-dependent DNA replication in the absence of a cyclin/CDK, and blocks the ability of PCNA to activateDNA polymerase δ, the principal replicative DNA polymerase. Expand
Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair
It is shown that p21 does not block PCNA-dependent nucleotide-excision repair, in contrast to its inhibition of simian virus 40 DNA replication, and the short gap-filling DNA synthesis by PC NA-dependent DNA polymerases δ and ɛ is less sensitive to inhibition by p21 than is long primer-extension synthesis. Expand
Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA
It is reported here that separate domains of p21 are responsible for interacting with and inhibiting the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA), and the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells. Expand
Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage.
This review will focus on the multiple functions of p21 in cell cycle regulation, apoptosis and gene transcription after DNA damage and briefly discuss the pathways and factors that have critical roles in p21 expression and activity. Expand
Activity and nature of p21(WAF1) complexes during the cell cycle.
  • K. Cai, B. Dynlacht
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1998
The data strengthen the notion that the G1-to-S phase transition in human fibroblasts occurs when the concentration of cyclin A/Cdk2 surpasses that of p21, and the use of multiple antibodies has enabled the study of the molecular architecture of p 21 complexes in vivo. Expand
p21waf1 can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases
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