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Updated: Feb 23, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The PWWP domain of the human oncogene WHSC1L1/NSD3 induces a metabolic shift toward fermentation
Germana B Rona1, Diego S G Almeida1, Anderson S Pinheiro1
1Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, 21941-909, Rio de Janeiro, RJ, Brazil.
Abstract:
WHSC1L1/NSD3, one of the most aggressive human oncogenes, has two isoforms derived from alternative splicing. Overexpression of long or short NSD3 is capable of transforming a healthy into a cancer cell. NSD3s, the short isoform, contains only a PWWP domain, a histone methyl-lysine reader involved in epigenetic regulation of gene expression. With the aim of understanding the NSD3s PWWP domain role in tumorigenesis, we used Saccharomyces cerevisiae as an experimental model. We identified the yeast protein Pdp3 that contains a PWWP domain that closely resembles NSD3s PWWP. Our results indicate that the yeast protein Pdp3 and human NSD3s seem to play similar roles in energy metabolism, leading to a metabolic shift toward fermentation. The swapping domain experiments suggested that the PWWP domain of NSD3s functionally substitutes that of yeast Pdp3, whose W21 is essential for its metabolic function.
Insights
The NSD3 oncogene
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- WHSC1L1/NSD3 is a potent human oncogene with two isoforms.
- Overexpression of either NSD3 isoform can induce cancer cell transformation.
- The short NSD3 isoform (NSD3s) possesses a PWWP domain crucial for epigenetic regulation.
Purpose of the Study:
- To investigate the role of the NSD3s PWWP domain in tumorigenesis.
- To utilize Saccharomyces cerevisiae as a model organism for studying NSD3 function.
- To understand the functional conservation of PWWP domains in metabolism.
Main Methods:
- Comparative analysis of human NSD3s and yeast Pdp3 PWWP domains.
- Functional assays in Saccharomyces cerevisiae.
- Domain swapping experiments between NSD3s and Pdp3.
Main Results:
- Identified yeast Pdp3 protein with a PWWP domain similar to human NSD3s.
- Demonstrated conserved roles of Pdp3 and NSD3s in energy metabolism, promoting fermentation.
- Confirmed functional substitution of yeast Pdp3's PWWP domain by human NSD3s' PWWP domain.
- Identified W21 in yeast Pdp3's PWWP domain as essential for its metabolic function.
Conclusions:
- The PWWP domain of NSD3 plays a conserved role in metabolic regulation relevant to tumorigenesis.
- Yeast Pdp3 serves as a functional model for studying NSD3 PWWP domain activity.
- Specific residues within the PWWP domain are critical for its metabolic function.
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