title: Molecular cloning of a translocation breakpoint hotspot in 22q11.
abstract: It has been well documented that 22q11 contains one of the most rearrangement-prone sites in the human genome, where the breakpoints of a number of constitutional translocations cluster. This breakage-sensitive region is located within one of the remaining unclonable gaps from the human genome project, suggestive of a specific sequence recalcitrant to cloning. In this study, we cloned a part of this gap and identified a novel 595-bp palindromic AT-rich repeat (PATRR). To date we have identified three translocation-associated PATRRs. They have common characteristics: (1) they are AT-rich nearly perfect palindromes, which are several hundred base pairs in length; (2) they possess non-AT-rich regions at both ends of the PATRR; (3) they display another nearby AT-rich region on one side of the PATRR. All of these features imply a potential for DNA secondary structure. Sequence analysis of unrelated individuals indicates no major size polymorphism, but shows minor nucleotide polymorphisms among individuals and cis-morphisms between the proximal and distal arms. Breakpoint analysis of various translocations indicates that double-strand-breakage (DSB) occurs at the center of the palindrome, often accompanied by a small symmetric deletion at the center. The breakpoints share only a small number of identical nucleotides between partner chromosomes. Taken together, these features imply that the DSBs are repaired through nonhomologous end joining or single-strand annealing rather than a homologous recombination pathway. All of these results support a previously proposed paradigm that unusual DNA secondary structure plays a role in the mechanism by which palindrome-mediated translocations occur.
authors.affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan. kura@fujita-hu.ac.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurahashi
authors.forename: Hidehito
authors.initials: H
authors.lastname: Inagaki
authors.forename: Eriko
authors.initials: E
authors.lastname: Hosoba
authors.forename: Takema
authors.initials: T
authors.lastname: Kato
authors.forename: Tamae
authors.initials: T
authors.lastname: Ohye
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kogo
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
mesh_terms: D020856:AT Rich Sequence; D000818:Animals; D001483:Base Sequence; D019457:Chromosome Breakage; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003001:Cloning, Molecular; D006224:Cricetinae; D004247:DNA / Q000737:chemistry / Q000235:genetics; D006801:Humans; D006822:Hybrid Cells; D051379:Mice; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic
chemical_list: D004247:DNA