title: PREVENTING THE CHROMOSOMAL TRANSLOCATIONS THAT CAUSE CANCER.
abstract: Approximately half of all cancers harbor chromosomal translocations that can either contribute to their origin or govern their subsequent behavior. Chromosomal translocations by definition can only occur when there are two DNA double-strand breaks (DSBs) on distinct chromosomes that are repaired heterologously. Thus, chromosomal translocations are by their very nature problems of DNA DSB repair. Such DNA DSBs can be from internal or external sources. Internal sources of DNA DSBs that can lead to translocations can occur are inappropriate immune receptor gene maturation during V(D)J recombination or heavy-chain switching. Other internal DNA DSBs can come from aberrant DNA structures, or are generated at collapsed and reversed replication forks. External sources of DNA DSBs that can generate chromosomal translocations are ionizing radiation and cancer chemotherapy. There are several known nuclear and chromatin properties that enhance translocations over homologous chromosome DSB repair. The proximity of the region of the heterologous chromosomes to each other increases translocation rates. Histone methylation events at the DSB also influence translocation frequencies. There are four DNA DSB repair pathways, but it appears that only one, alternative non-homologous end-joining (a-NHEJ) can mediate chromosomal translocations. The rate-limiting, initial step of a-NHEJ is the binding of poly-adenosine diphosphate ribose polymerase 1 (PARP1) to the DSB. In our investigation of methods for preventing oncogenic translocations, we discovered that PARP1 was required for translocations. Significantly, the clinically approved PARP1 inhibitors can block the formation of chromosomal translocations, raising the possibility for the first time that secondary oncogenic translocations can be reduced in high risk patients.
authors.affiliation: GAINESVILLE, FLORIDA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
authors.affiliation: GAINESVILLE, FLORIDA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Williamson
authors.affiliation: GAINESVILLE, FLORIDA.
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: GAINESVILLE, FLORIDA.
authors.forename: Jac
authors.initials: J
authors.lastname: Nickoloff
mesh_terms: D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors; D014178:Translocation, Genetic
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1