MDM2 promotes genome instability by ubiquitinating the transcription factor HBP1

Oncogene
Zhengyi CaoXiaowei Zhang

Abstract

Genome instability is a common feature of tumor cells, and the persistent presence of genome instability is a potential mechanism of tumorigenesis. The E3 ubiquitin ligase MDM2 is intimately involved in genome instability, but its mechanisms are unclear. Our data demonstrated that the transcription factor HBP1 is a target of MDM2. MDM2 facilitates HBP1 proteasomal degradation by ubiquitinating HBP1, regardless of p53 status, thus attenuating the transcriptional inhibition of HBP1 in the expression of its target genes, such as the DNA methyltransferase DNMT1 and histone methyltransferase EZH2, which results in global DNA hypermethylation and histone hypermethylation and ultimately genome instability. The repression of HBP1 by MDM2 finally promotes cell growth and tumorigenesis. Next, we thoroughly explored the regulatory mechanism of the MDM2/HBP1 axis in DNA damage repair following ionizing radiation. Our data indicated that MDM2 overexpression-mediated repression of HBP1 delays DNA damage repair and causes cell death in a p53-independent manner. This investigation elucidated the mechanism of how MDM2 promotes genome instability and enhances tumorigenesis in the absence of p53, thus providing a theoretical and experimental basi...Continue Reading

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Citations

Jun 14, 2020·Signal Transduction and Targeted Therapy·Ling ChenYongguang Tao
Aug 4, 2020·Seminars in Cancer Biology·Michael J DuffyJohn Crown
Feb 3, 2021·International Journal of Molecular Sciences·Cristina Herrera-ParienteLeticia Moreira
Jan 6, 2021·Biomolecules·Konstantinos KarakostisVanesa Olivares-Illana
Apr 1, 2021·Journal of Experimental & Clinical Cancer Research : CR·Hai HuangMyoung Ok Kim
Apr 3, 2021·Journal of Experimental & Clinical Cancer Research : CR·Zhengyi CaoXiaowei Zhang
Apr 24, 2021·Genes & Development·Alyssa M KleinCarol Prives

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Methods Mentioned

BETA
ubiquitination
PCR
co-immunoprecipitation
immunoprecipitation
pulldown
pulled down
transfection
FCS
xenograft
transgenic

Software Mentioned

Image J
GraphPad Prism

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