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Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions

Roehl, Angelika C., Vogt, Julia, Mussotter, Tanja, Zickler, Antje N., Spöti, Helene, Högel, Josef, Chuzhanova, Nadia A., Wimmer, Katharina, Kluwe, Lan, Mautner, Victor-Felix, Cooper, David Neil and Kehrer-Sawatzki, Hildegard 2010. Intrachromosomal mitotic nonallelic homologous recombination is the major molecular mechanism underlying type-2 NF1 deletions. Human Mutation 31 (10) , pp. 1163-1173. 10.1002/humu.21340

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Abstract

Nonallelic homologous recombination (NAHR) is responsible for the recurrent rearrangements that give rise to genomic disorders. Although meiotic NAHR has been investigated in multiple contexts, much less is known about mitotic NAHR despite its importance for tumorigenesis. Because type-2 NF1 microdeletions frequently result from mitotic NAHR, they represent a good model in which to investigate the features of mitotic NAHR. We have used microsatellite analysis and SNP arrays to distinguish between the various alternative recombinational possibilities, thereby ascertaining that 17 of 18 type-2 NF1 deletions, with breakpoints in the SUZ12 gene and its highly homologous pseudogene, originated via intrachromosomal recombination. This high proportion of intrachromosomal NAHR causing somatic type-2 NF1 deletions contrasts with the interchromosomal origin of germline type-1 NF1 microdeletions, whose breakpoints are located within the NF1-REPs (low-copy repeats located adjacent to the SUZ12 sequences). Further, meiotic NAHR causing type-1 NF1 deletions occurs within recombination hotspots characterized by high GC-content and DNA duplex stability, whereas the type-2 breakpoints associated with the mitotic NAHR events investigated here do not cluster within hotspots and are located within regions of significantly lower GC-content and DNA stability. Our findings therefore point to fundamental mechanistic differences between the determinants of mitotic and meiotic NAHR.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > R Medicine (General)
Uncontrolled Keywords: neurofibromatosis type 1 ; NF1 ; Mitotic nonallelic Momologous recombination ; NAHR ; Microdeletion ; Tumorigenesis ; Alu ; non-B DNA
Publisher: John Wiley & Sons
ISSN: 1059-7794
Last Modified: 04 Jun 2017 03:33
URI: http://orca.cf.ac.uk/id/eprint/22799

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