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HSP90 Shapes the Consequences of Human Genetic Variation.

Authors
  • Karras, Georgios I1
  • Yi, Song2
  • Sahni, Nidhi2
  • Fischer, Máté3
  • Xie, Jenny4
  • Vidal, Marc2
  • D'Andrea, Alan D4
  • Whitesell, Luke5
  • Lindquist, Susan6
  • 1 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: [email protected]
  • 2 Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 4 Center for DNA Damage and Repair and Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Electronic address: [email protected]
  • 6 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
Type
Published Article
Journal
Cell
Publication Date
Feb 23, 2017
Volume
168
Issue
5
Identifiers
DOI: 10.1016/j.cell.2017.01.023
PMID: 28215707
Source
Medline
Keywords
License
Unknown

Abstract

HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.

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