Gregory J. Brunette, Mohd A. Jamalruddin, Robert A. Baldock, Nathan L. Clark, and Kara A. Bernstein

PNAS September 24, 2019 116 (39) 19593-19599

GENETICS

Significance

Genome stability is maintained through conserved DNA repair pathways. By analyzing evolutionary relationships between genes that mediate DNA repair, we show that functional relationships between DNA repair genes are reflected in the variation of their evolutionary rates. Here we ranked mammalian genes for coevolution with 6 DNA repair pathways. Direct comparison to genetic screens for DNA repair factors indicates that our evolution-based screen is comparable, if not superior, to traditional screening approaches. As a proof of principle, we identified a role for the gene DDIAS in double-strand break (DSB) repair. DDIAS depletion results in DSB accumulation, increased checkpoint signaling, and defective homologous recombination. Our results reveal that evolutionary analysis is a powerful tool to uncover DNA repair factors.

Abstract

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.

See https://www.pnas.org/content/116/39/19593

Figure 2: Evolutionary rate covariation between HR genes. The ERC values between HR gene pairs in each DNA processing step were calculated and plotted using a heat map (ranging from 0 [no covariation] to 1 [positive covariation]). Genes are hierarchically clustered.