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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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DNA-Damage-Induced Alternative Splicing of p53.

Jing Chen1,2, Dadong Zhang3, Xiaodi Qin3

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Cancers
|January 15, 2021
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DNA damage triggers alternative splicing of TP53, creating the p53β isoform. This isoform is crucial for inducing cellular senescence, revealing a new layer of p53 protein regulation beyond its half-life.

Keywords:
agingcancerprotein interactiontranscription

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Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Cellular responses to DNA damage are critical for preventing mutagenesis and disease.
  • TP53 is a key tumor suppressor gene frequently mutated in human cancers, regulating stress responses and cell fate.
  • The established model for p53 induction post-DNA damage focuses on increased protein half-life.

Purpose of the Study:

  • To investigate the role of translational regulation in p53 induction after DNA damage.
  • To uncover novel mechanisms of p53 regulation beyond the traditional half-life model.
  • To elucidate the functional divergence between full-length (FL) p53 and its newly discovered beta isoform (p53β).

Main Methods:

  • Investigated DNA-damage-induced alternative splicing (AS) of p53 pre-mRNA.
  • Identified the generation of the p53β isoform RNA and protein.
  • Analyzed the differential transcriptome and protein interactome of FL p53 versus p53β.

Main Results:

  • Discovered a DNA-damage-induced AS pathway affecting p53 and other genes.
  • Demonstrated that p53β RNA and protein are specifically required for inducing cellular senescence markers after ionizing irradiation (IR).
  • Identified unique characteristics of p53β, including a 10-amino-acid tail, potentially explaining functional differences from FL p53.

Conclusions:

  • The induction of p53 after DNA damage involves critical translational regulation and alternative splicing, not solely increased protein half-life.
  • The p53β isoform plays a distinct role in promoting cellular senescence, contrasting with the apoptotic function often associated with FL p53.
  • Understanding the p53β isoform and its interactome is essential for deciphering p53's complex roles in cancer and disease.