Further delineation of nonhomologous-based recombination and evidence for subtelomeric segmental duplications in 1p36 rearrangements

Autor(es)

D'Angelo, Carla S. ^[1] ; Gajecka, Marzena ^{[2, 3]} ; Kim, Chong A. ^[4] ; Gentles, Andrew J. ^[5] ; Glotzbach, Caron D. ^[6] ; Shaffer, Lisa G. ^[6] ; Koiffmann, Celia P. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Genet & Biol Evolut, Ctr Estudos Genoma Humano, Inst Biociencias, BR-05508900 Sao Paulo - Brazil

^[2] Washington State Univ, WWAMI Med Educ Program, Sch Mol Biosci, Spokane, WA 99202 - USA

^[3] Polish Acad Sci, Inst Human Genet, PL-61713 Poznan - Poland

^[4] Univ Sao Paulo, Genet Unit, Dept Pediat, Children Inst, BR-05403000 Sao Paulo - Brazil

^[5] Stanford Univ, Sch Med, Stanford, CA 94305 - USA

^[6] Signature Genom Labs, Spokane, WA 99202 - USA

• Tipo de documento: Artigo Científico
• Fonte: Human Genetics; v. 125, n. 5-6, p. 551-563, JUN 2009.
• Citações Web of Science: 19

Resumo

The mechanisms involved in the formation of subtelomeric rearrangements are now beginning to be elucidated. Breakpoint sequencing analysis of 1p36 rearrangements has made important contributions to this line of inquiry. Despite the unique architecture of segmental duplications inherent to human subtelomeres, no common mechanism has been identified thus far and different nonexclusive recombination-repair mechanisms seem to predominate. In order to gain further insights into the mechanisms of chromosome breakage, repair, and stabilization mediating subtelomeric rearrangements in humans, we investigated the constitutional rearrangements of 1p36. Cloning of the breakpoint junctions in a complex rearrangement and three non-reciprocal translocations revealed similarities at the junctions, such as microhomology of up to three nucleotides, along with no significant sequence identity in close proximity to the breakpoint regions. All the breakpoints appeared to be unique and their occurrence was limited to non-repetitive, unique DNA sequences. Several recombination- or cleavage-associated motifs that may promote non-homologous recombination were observed in close proximity to the junctions. We conclude that NHEJ is likely the mechanism of DNA repair that generates these rearrangements. Additionally, two apparently pure terminal deletions were also investigated, and the refinement of the breakpoint regions identified two distinct genomic intervals similar to 25-kb apart, each containing a series of 1p36 specific segmental duplications with 90-98% identity. Segmental duplications can serve as substrates for ectopic homologous recombination or stimulate genomic rearrangements. (AU)

• Processo FAPESP: 04/10380-6 - Sindrome da monossomia 1p36: investigacao de delecoes em 1p36 e de suas correlacoes genotipo-fenotipo.
• Beneficiário: Carla Sustek D'Angelo
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 98/14254-2 - Centro de Estudos do Genoma Humano
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs