A missense variant effect map for the human tumor-suppressor protein CHK2
The tumor suppressor CHEK2 encodes the serine/threonine protein kinase CHK2 which, upon DNA damage, is important for pausing the cell cycle, initiating DNA repair, and inducing apoptosis. CHK2 phosphorylation of the tumor suppressor BRCA1 is also important for mitotic spindle assembly and chromosomal stability. Consistent with its cell-cycle checkpoint role, both germline and somatic variants in CHEK2 have been linked to breast and other cancers. Over 90% of clinical germline CHEK2 missense variants are classified as variants of uncertain significance, complicating diagnosis of CHK2-dependent cancer. We therefore sought to test the functional impact of all possible missense variants in CHK2. Using a scalable multiplexed assay based on the ability of human CHK2 to complement DNA sensitivity of Saccharomyces cerevisiae cells lacking the CHEK2 ortholog, RAD53, we generated a systematic "missense variant effect map" for CHEK2 missense variation. The map reflects known biochemical features of CHK2 while offering new biological insights. It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants.
Authors
- Douglas M. Fowler (ORCID: https://orcid.org/0000-0001-7614-1713)
- Song Sun (ORCID: https://orcid.org/0000-0003-4653-8706)
- Britt Johnson (ORCID: https://orcid.org/0000-0003-1883-5201)
- Fergus J. Couch (ORCID: https://orcid.org/0000-0001-9417-9985)
- Jochen Weile (ORCID: https://orcid.org/0000-0003-1628-9390)
- Rosanna Jiang
- Jason Reuter (ORCID: https://orcid.org/0000-0002-0651-3742)
- Rayna Hamilton
- Nishka Kishore (ORCID: https://orcid.org/0000-0002-9219-4310)
- Maria Nguyen (ORCID: https://orcid.org/0000-0003-2441-4948)
- Roujia Li
- Jennifer N. Dines (ORCID: https://orcid.org/0000-0003-1649-2006)
- Rick A.C.M. Boonen
- Frederick P. Roth (ORCID: https://orcid.org/0000-0002-6628-649X)
- Haico van Attikum (ORCID: https://orcid.org/0000-0001-8590-0240)
- Marinella Gebbia (ORCID: https://orcid.org/0000-0002-2550-2141)
- Michelle Gavac
- Alexander Wahl
- Daniel Zimmerman (ORCID: https://orcid.org/0009-0003-2264-6769)
Institutions
- University of Washington (US)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Leiden University Medical Center (NL)
- Mayo Clinic in Arizona (US)
- Invitae (United States) (US)
- Woods Hole Oceanographic Institution (US)
Publication Details
- Journal
- The American Journal of Human Genetics
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.ajhg.2024.10.013
- Citations
- 15
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 3.51
Funders
- Breast Cancer Research Foundation
- Government of Canada
- Canada Excellence Research Chairs, Government of Canada
- National Institutes of Health
- Canadian Institutes of Health Research
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Cancer Institute