Recessive cancer genes engage in negative genetic interactions with their functional paralogs

Cell Rep. 2013 Dec 26;5(6):1519-26. doi: 10.1016/j.celrep.2013.11.033. Epub 2013 Dec 19.

Abstract

Cancer genetic heterogeneity offers a wide repertoire of molecular determinants to be screened as therapeutic targets. Here, we identify potential anticancer targets by exploiting negative genetic interactions between genes with driver loss-of-function mutations (recessive cancer genes) and their functionally redundant paralogs. We identify recessive genes with additional copies and experimentally test our predictions on three paralogous pairs. We confirm digenic negative interactions between two cancer genes (SMARCA4 and CDH1) and their corresponding paralogs (SMARCA2 and CDH3). Furthermore, we identify a trigenic negative interaction between the cancer gene DNMT3A, its functional paralog DNMT3B, and a third gene, DNMT1, which encodes the only other human DNA-methylase domain. Although our study does not exclude other causes of synthetic lethality, it suggests that functionally redundant paralogs of cancer genes could be targets in anticancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • Epistasis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Genes, Neoplasm*
  • Genes, Recessive*
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Antigens, CD
  • CDH1 protein, human
  • CDH3 protein, human
  • Cadherins
  • Nuclear Proteins
  • SMARCA2 protein, human
  • Transcription Factors
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B
  • DNMT1 protein, human
  • SMARCA4 protein, human
  • DNA Helicases