title: The structure of ends determines the pathway choice and Mre11 nuclease dependency of DNA double-strand break repair.
abstract: The key event in the choice of repair pathways for DNA double-strand breaks (DSBs) is the initial processing of ends. Non-homologous end joining (NHEJ) involves limited processing, but homology-dependent repair (HDR) requires extensive resection of the 5' strand. How cells decide if an end is channeled to resection or NHEJ is not well understood. We hypothesize that the structure of ends is a major determinant and tested this hypothesis with model DNA substrates in Xenopus egg extracts. While ends with normal nucleotides are efficiently channeled to NHEJ, ends with damaged nucleotides or bulky adducts are channeled to resection. Resection is dependent on Mre11, but its nuclease activity is critical only for ends with 5' bulky adducts. CtIP is absolutely required for activating the nuclease-dependent mechanism of Mre11 but not the nuclease-independent mechanism. Together, these findings suggest that the structure of ends is a major determinant for the pathway choice of DSB repair and the Mre11 nuclease dependency of resection.
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Shuren
authors.initials: S
authors.lastname: Liao
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Tammaro
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA Hong.Yan@fccc.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
mesh_terms: D000818:Animals; D002457:Cell Extracts / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D000076228:MRE11 Homologue Protein; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000737:chemistry / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics*; D014981:Xenopus / Q000235:genetics; D029867:Xenopus Proteins / Q000235:genetics*
chemical_list: D002457:Cell Extracts; D004268:DNA-Binding Proteins; C510917:Mre11 protein, Xenopus; D009711:Nucleotides; D029867:Xenopus Proteins; D000076228:MRE11 Homologue Protein