Evolution-based screening enables genome-wide prioritization and discovery of DNA repair genes

DNA repair is critical for genome stability and is maintained through conserved pathways. Traditional genome-wide mammalian screens are both expensive and laborious. However, computational approaches circumvent these limitations and are a powerful tool to identify new DNA repair factors. By analyzin...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 39; pp. 19593 - 19599
Main Authors:	Brunette, Gregory J., Jamalruddin, Mohd A., Baldock, Robert A., Clark, Nathan L., Bernstein, Kara A.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 24-09-2019
Subjects:	Anemia Animals Apoptosis Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Biological evolution Biological Sciences Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Coevolution Computer applications Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded DNA damage DNA repair DNA Repair - genetics Double-strand break repair Evolution, Molecular Evolutionary genetics Fanconi syndrome Genes Genetic screening Genome-Wide Association Study - methods Genomes Genomic Instability - genetics Homologous recombination Homologous Recombination - genetics Homology Humans Kinases Mammals Rad51 Recombinase - genetics Rad51 Recombinase - metabolism Repair Screening evolution homologous recombination DDIAS DNA repair genome integrity
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Summary:	DNA repair is critical for genome stability and is maintained through conserved pathways. Traditional genome-wide mammalian screens are both expensive and laborious. However, computational approaches circumvent these limitations and are a powerful tool to identify new DNA repair factors. By analyzing the evolutionary relationships between genes in the major DNA repair pathways, we uncovered functional relationships between individual genes and identified partners. Here we ranked 17,487 mammalian genes for coevolution with 6 distinct DNA repair pathways. Direct comparison to genetic screens for homologous recombination or Fanconi anemia factors indicates that our evolution-based screen is comparable, if not superior, to traditional screening approaches. Demonstrating the utility of our strategy, we identify a role for the DNA damage-induced apoptosis suppressor (DDIAS) gene in double-strand break repair based on its coevolution with homologous recombination. DDIAS knockdown results in DNA double-strand breaks, indicated by ATM kinase activation and 53BP1 foci induction. Additionally, DDIAS-depleted cells are deficient for homologous recombination. Our results reveal that evolutionary analysis is a powerful tool to uncover novel factors and functional relationships in DNA repair.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved August 16, 2019 (received for review April 16, 2019) Author contributions: G.J.B., R.A.B., N.L.C., and K.A.B. designed research; G.J.B., M.A.J., and N.L.C. performed research; N.L.C. contributed new reagents/analytic tools; G.J.B., N.L.C., and K.A.B. analyzed data; and G.J.B., N.L.C., and K.A.B. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1906559116