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PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells.

08:00 EDT 2nd April 2019 | BioPortfolio

Summary of "PCNA-Mediated Degradation of p21 Coordinates the DNA Damage Response and Cell Cycle Regulation in Individual Cells."

To enable reliable cell fate decisions, mammalian cells need to adjust their responses to dynamically changing internal states by rewiring the corresponding signaling networks. Here, we combine time-lapse microscopy of endogenous fluorescent reporters with computational analysis to understand at the single-cell level how the p53-mediated DNA damage response is adjusted during cell cycle progression. Shape-based clustering revealed that the dynamics of the CDK inhibitor p21 diverges from the dynamics of its transcription factor p53 during S phase. Using mathematical modeling, we predict and experimentally validate that S phase-specific degradation of p21 by PCNA-CRL4 is sufficient to explain these heterogeneous responses. This highlights how signaling pathways and cell regulatory networks intertwine to adjust the cellular response to the individual needs of a given cell.

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Journal Details

This article was published in the following journal.

Name: Cell reports
ISSN: 2211-1247
Pages: 48-58.e7

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Medical and Biotech [MESH] Definitions

A serine/threonine-specific protein kinase which is encoded by the CHEK1 gene in humans. Checkpoint kinase 1 (also known as Chk1) coordinates DNA damage response and cell cycle checkpoint response. Under these conditions, activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death, to prevent damaged cells from progressing through the cell cycle.

Nuclear antigen with a role in DNA synthesis, DNA repair, and cell cycle progression. PCNA is required for the coordinated synthesis of both leading and lagging strands at the replication fork during DNA replication. PCNA expression correlates with the proliferation activity of several malignant and non-malignant cell types.

A NIMA-related kinase that functions in CELL CYCLE regulation, the control of CILIA assembly, and CENTROSOME duplication. It is activated at G2 PHASE CELL CYCLE CHECKPOINTS in response to DNA DAMAGE.

A nuclear and cytoplasmic protein that associates with KINETOCHORES and contains a C-terminal TUDOR DOMAIN. It plays a critical role in the cellular response to DNA DAMAGE and localizes to DOUBLE-STRAND DNA BREAKS. It may also function in M PHASE CELL CYCLE CHECKPOINTS and as an enhancer of TUMOR SUPPRESSOR PROTEIN P53-mediated transcriptional activation.

Enzyme activated in response to DNA DAMAGE involved in cell cycle arrest. The gene is located on the long (q) arm of chromosome 22 at position 12.1. In humans it is encoded by the CHEK2 gene.

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