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  3. On the Mechanism of Hyperthermia-Induced BRCA2 Protein Degradation

On the Mechanism of Hyperthermia-Induced BRCA2 Protein Degradation

  • Cancers (Basel). 2019 Jan 15;11(1):97. doi: 10.3390/cancers11010097.
Nathalie van den Tempel 1,  Alex N Zelensky 2,  Hanny Odijk 3,  Charlie Laffeber 4,  Christine K Schmidt 5 6,  Inger Brandsma 7,  Jeroen Demmers 8,  Przemek M Krawczyk 9,  Roland Kanaar 10
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. n.van.den.tempel@umcg.nl.
  • 2 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. o.zelenskyy@erasmusmc.nl.
  • 3 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. j.odijk@erasmusmc.nl.
  • 4 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. c.laffeber@erasmusmc.nl.
  • 5 Department of Biochemistry, The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK. christine.schmidt@manchester.ac.uk.
  • 6 Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK. christine.schmidt@manchester.ac.uk.
  • 7 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. inger.brandsma@gmail.com.
  • 8 Department of Biochemistry, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. j.demmers@erasmusmc.nl.
  • 9 Department of Cell Biology and Histology Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. p.krawczyk@amc.uva.nl.
  • 10 Department of Molecular Genetics, Oncode Institute, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. r.kanaar@erasmusmc.nl.
PMID: 30650591 DOI: 10.3390/cancers11010097
Abstract

The DNA damage response (DDR) is a designation for a number of pathways that protects our DNA from various damaging agents. In normal cells, the DDR is extremely important for maintaining genome integrity, but in Cancer cells these mechanisms counteract therapy-induced DNA damage. Inhibition of the DDR could therefore be used to increase the efficacy of anti-cancer treatments. Hyperthermia is an example of such a treatment-it inhibits a sub-pathway of the DDR, called homologous recombination (HR). It does so by inducing proteasomal degradation of BRCA2 -one of the key HR factors. Understanding the precise mechanism that mediates this degradation is important for our understanding of how hyperthermia affects therapy and how homologous recombination and BRCA2 itself function. In addition, mechanistic insight into the process of hyperthermia-induced BRCA2 degradation can yield new therapeutic strategies to enhance the effects of local hyperthermia or to inhibit HR. Here, we investigate the mechanisms driving hyperthermia-induced BRCA2 degradation. We find that BRCA2 degradation is evolutionarily conserved, that BRCA2 stability is dependent on HSP90, that ubiquitin might not be involved in directly targeting BRCA2 for protein degradation via the Proteasome, and that BRCA2 degradation might be modulated by oxidative stress and radical scavengers.

Keywords

BRCA2; HSP90; RAD51; SILAC mass spectrometry; homologous recombination; hyperthermia; protein degradation; reactive oxygen species; ubiquitin.

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