title: BRCA2 is needed for both repair and cell cycle arrest in mammalian cells exposed to S23906, an anticancer monofunctional DNA binder.
abstract: Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models. S23906 forms bulky monofunctional DNA adducts in the minor groove which leads to destabilization of the double-stranded helix. We now report that S23906 induces formation of DNA double strand breaks that are processed through homologous recombination (HR) but not Non-Homologous End-Joining (NHEJ) repair. Interestingly, S23906 exposure was accompanied by a higher sensitivity of BRCA2-deficient cells compared to other HR deficient cell lines and by an S-phase accumulation in wild-type (wt), but not in BRCA2-deficient cells. Recently, we have shown that S23906-induced S phase arrest was mediated by the checkpoint kinase Chk1. However, its activated phosphorylated form is equally induced by S23906 in wt and BRCA2-deficient cells, likely indicating a role for BRCA2 downstream of Chk1. Accordingly, override of the S phase arrest by either 7-hydroxystaurosporine (UCN-01) or AZD7762 potentiates the cytotoxic activity of S23906 in wt, but not in BRCA2-deficient cells. Together, our findings suggest that the pronounced sensitivity of BRCA2-deficient cells to S23906 is due to both a defective S-phase arrest and the absence of HR repair. Tumors with deficiencies for proteins involved in HR, and BRCA2 in particular, may thus show increased sensitivity to S23906, thereby providing a rationale for patient selection in clinical trials.
authors.affiliation: a Laboratory of Cancer Biology and Therapeutics ; Centre de Recherche Saint-Antoine ; Paris , France.
authors.forename: Céline J
authors.initials: CJ
authors.lastname: Rocca
authors.forename: Daniele G
authors.initials: DG
authors.lastname: Soares
authors.forename: Hana
authors.initials: H
authors.lastname: Bouzid
authors.forename: João A P
authors.initials: JA
authors.lastname: Henriques
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
authors.forename: Alexandre E
authors.initials: AE
authors.lastname: Escargueil
mesh_terms: D000175:Acronine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000494:pharmacology; D024682:BRCA2 Protein / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D059766:DNA End-Joining Repair / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans
chemical_list: C560585:1,2-diacetoxy-3,14-dihydro-3,3,14-trimethyl-6-methoxy-7H-benz(b)pyrano(3,2-d)acridin-7-one; D018906:Antineoplastic Agents, Alkylating; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000175:Acronine
keywords: ATR, Ataxia telangiectasia- and RAD3-related; DNA alkylators; DNA double strand breaks; DNA replication; DSBs, Double Strand Breaks; FA, Fanconi Anemia; GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; HR, Homologous Recombination; HU, Hydroxyurea; Homologous recombination; ICLs, Inter-strand Crosslinks; NER, Nucleotide Excision Repair; NHEJ, Non-Homologous End-Joining; TCR, Transcription-Coupled Repair; UCN-01, 7-hydroxystaurosporine.; checkpoint control