title: Synthetic lethality and cancer: cohesin and PARP at the replication fork.
abstract: Cohesins are mutated in a significant number of tumors of various types making them attractive targets for chemotherapeutic intervention. However, cohesins have a spectrum of cellular roles including sister chromatid cohesion, transcription, replication, and repair. Which of these roles are central to cancer biology and which roles can be exploited for therapeutic intervention? Genetic interaction networks in yeast have identified synthetic lethal interactions between mutations in cohesin and replication fork mediators. These interactions are conserved in worms and in human cells suggesting that inhibition of replication fork stability mediators such as poly (ADP-ribose) polymerase (PARP) could result in the specific killing of tumors with cohesin mutations. These findings also highlight the utility of genetic interaction networks in model organisms for the identification of clinically relevant interactions. Here, we review this type of approach, emphasizing the power of synthetic lethal interactions to reveal new avenues for developing cancer therapeutics.
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
authors: Nigel J
authors: NJ
authors: O'Neil
authors: Derek M
authors: DM
authors: van Pel
authors: Philip
authors: P
authors: Hieter
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D020090:Chromosome Segregation; D004261:DNA Replication / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D000097722:Cohesins; C499320:PARP1 protein, human