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Investigating the Effects of Cancer Mutations on Mre11 Function and the DNA Damage Response
Author(s) -
Harris Caitlin,
Savas Jessica,
Shanle Erin Karina
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.457.6
Subject(s) - dna damage , dna repair , biology , genetics , rad50 , yeast , mutation , mutant , dna , point mutation , cancer , conserved sequence , gene , dna binding protein , transcription factor , base sequence
When DNA is damaged, a DNA damage response (DDR) pathway is initiated to prevent mutations from being passed on to daughter cells. The MRN complex in humans (MRX in yeast) functions to start the DDR pathway by detecting DNA damage and is comprised of Mre11, Rad50, and Nbs1 in humans. Although mutations in members of the MRN complex pre‐dispose individuals to cancer, the functional effects of Mre11 cancer mutations have not been well characterized. The goal of this project was to investigate the effects of Mre11 cancer mutations on the DDR pathway using yeast‐based assays because the complex is highly conserved in eukaryotes. Using a database of human tumor mutations, we identified 135 cancer mutations in human Mre11, 46 of which occurred at residues that are conserved between yeast and human. A subset of these mutations were screened for functional effects in yeast by creating the cancer mutations at the conserved residues in yeast Mre11. Yeast expressing wild‐type or mutant Mre11 were then assessed for DNA damage sensitivity using ultraviolet light and methyl methanesulfonate. Results indicate that N‐terminal point mutations at in yeast Mre11 do not confer sensitivity to DNA damage in yeast cells suggesting that these regions may have conserved sequence without conserved function. Using yeast‐based assays, cancer mutations can rapidly be screened for functional effects on DDR pathways. Support or Funding Information Longwood University Faculty Research and Development Grants This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .