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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A role of p73 in mitotic exit
Paola Merlo1, Marcella Fulco, Antonio Costanzo
1Laboratory of Gene Expression, Fondazione Andrea Cesalpino, 00161 Rome Italy.
Abstract:
The p53-related p73 proteins regulate developmental processes, cell growth, and DNA damage response. p73 function is regulated by post-translational modifications and protein-protein interactions. At the G2/M transition, p73 is phosphorylated at Thr-86 by the p34cdc2/cyclin B complex; this is associated with its exclusion from condensed chromosomes and loss of DNA binding and transcriptional activation ability. Here we showed that p73 hypo-phosphorylated species reappear during mitotic exit, concomitant with p73 relocalization to telophase nuclei and recovered ability to activate transcription. Functional knock-out of p73 gene expression by small interfering RNAs (siRNAs) alters mitotic progression, yielding an increase of ana-telophase cells, the accumulation of aberrant late mitotic figures, and the appearance of abnormalities in the subsequent interphase. This p73 activity at the M-to-G1 transition is mediated by its transactivating function because expression of the transcription dominant negative mutant p73DD induces the same mitotic exit phenotype. We also found that the cyclin-dependent kinase inhibitor Kip2/p57 gene is a specific target of p73 regulation during mitotic exit and re-entry into G1. Both knock-out of p73 gene expression by siRNAs and abrogation of p73-dependent transcription by the p73DD mutant abrogate Kip2/p57 increase at the M-to-G1 transition. Moreover, similar abnormalities (e.g. delay in late mitotic stages with the accumulation of aberrant ana-telophase figures, and abnormalities in the following interphase) are observed in cultures in which the expression of Kip2/p57 is abrogated by siRNAs. These results identify a novel p73-Kip2/p57 pathway that coordinates mitotic exit and transition to G1.
Insights
The p73 protein regulates cell cycle progression and gene expression during mitotic exit. Its newly identified pathway with Kip2/p57 coordinates the transition from mitosis to the G1 phase.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- p73 proteins are crucial regulators of cell growth, development, and DNA damage response.
- p73 activity is modulated by post-translational modifications and protein interactions, impacting its DNA binding and transcriptional functions.
- During mitosis, p73 phosphorylation by p34cdc2/cyclin B leads to chromosome exclusion and loss of transcriptional activity.
Purpose of the Study:
- To investigate the role of p73 during mitotic exit and its transition to the G1 phase.
- To identify specific p73 target genes involved in regulating mitotic exit.
- To elucidate the novel p73-Kip2/p57 pathway coordinating cell cycle progression.
Main Methods:
- Utilized small interfering RNAs (siRNAs) for functional gene knockout of p73 and Kip2/p57.
- Employed a transcription dominant-negative mutant p73DD to assess transactivating function.
- Analyzed mitotic progression, cell cycle abnormalities, and gene expression changes using microscopy and molecular assays.
Main Results:
- Hypo-phosphorylated p73 species reappear during mitotic exit, relocalize to telophase nuclei, and regain transcriptional activity.
- p73 knockout or functional abrogation disrupts mitotic progression, increasing ana-telophase cells and causing interphase abnormalities.
- The cyclin-dependent kinase inhibitor Kip2/p57 is identified as a direct transcriptional target of p73 during mitotic exit and G1 re-entry.
Conclusions:
- p73 plays a critical role in coordinating the M-to-G1 transition through its transactivating function.
- A novel p73-Kip2/p57 regulatory pathway is identified, essential for proper mitotic exit and G1 phase entry.
- Dysregulation of this pathway leads to mitotic abnormalities and subsequent interphase defects, highlighting its importance in cell cycle control.
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