Carcinogens induce reversion of the mouse pink-eyed unstable mutation

Schiestl, Robert H.; Aubrecht, Jiri; Khogali, Fathia; Carls, Nicholas

doi:10.1073/pnas.94.9.4576

Cited by 75 publications

(32 citation statements)

References 68 publications

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“…Tandem repeats are known to be highly unstable in both prokaryotes (Feschenko and Lovett, 1998) and mammals (Schiestl et al, 1997). There are several models to explain the deletion of one copy of a duplication by homologous recombination such as that observed in p un (Schiestl et al, 1997). In any model, recombination could occur within the duplicated unit to restore the wildtype sequence arrangement, consistent with our finding of sequence identity between DNA from wildtype mice and DNA from revertant mice.…”

Section: Pearl Reversionsupporting

confidence: 86%

“…This apparent exact loss of one duplicated unit (Fig. 2) in revertant mice strongly suggests an involvement of homologous recombination between two duplicated regions in the reversion process, similar to that postulated in the pink-eyed unstable (p un ) (Gondo et al, 1993;Schiestl et al, 1997) and HPRT (Helleday et al, 1998;Yang et al, 1988) reversions. Tandem repeats are known to be highly unstable in both prokaryotes (Feschenko and Lovett, 1998) and mammals (Schiestl et al, 1997).…”

Section: Pearl Reversionsupporting

confidence: 65%

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Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Rigatti

Novak

et al. 2000

Genomics

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The mouse hypopigmentation mutant pearl is an established model for Hermansky-Pudlak syndrome (HPS), a genetically heterogenous disease with misregulation of the biogenesis/function of melanosomes, lysosomes, and platelet dense granules. The pearl (Ap3b1) gene encodes the ␤3A subunit of the AP-3 adaptor complex, which regulates vesicular trafficking. The genomic structure of the normal Ap3b1 gene includes 25 introns and a putative promoter sequence. The original pearl (pe) mutation, which has an unusually high reversion rate on certain strain backgrounds, has been postulated to be caused by insertion of a transposable element. Indeed, the mutation contains a 215-bp partial mouse transposon at the junction point of a large tandem genomic duplication of 6 exons and associated introns. At the cDNA level, three pearl mutations (pearl, pearl-8J, and pearl-9J) are caused by deletions or duplications of a complete exon(s).

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Section: Pearl Reversionsupporting

confidence: 86%

Section: Pearl Reversionsupporting

confidence: 65%

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Rigatti

Novak

et al. 2000

Genomics

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“…The p un mice carry a natural duplication in a gene that controls pigmentation and have been used in studies of damage-induced recombination (e.g., refs. [46][47][48]. An important difference between p un and FYDR mice is that in p un mice, only recombination events that arise during development can be detected, whereas recombination events that occur both during development as well as in adult tissues can be detected in FYDR mice.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous mitotic homologous recombination at an enhanced yellow fluorescent protein (EYFP) cDNA direct repeat in transgenic mice

Hendricks

Almeida²,

Stitt³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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A transgenic mouse has been created that provides a powerful tool for revealing genetic and environmental factors that modulate mitotic homologous recombination. The fluorescent yellow directrepeat (FYDR) mice described here carry two different copies of expression cassettes for truncated coding sequences of the enhanced yellow fluorescent protein (EYFP), arranged in tandem. Homologous recombination between these repeated elements can restore full-length EYFP coding sequence to yield a fluorescent phenotype, and the resulting fluorescent recombinant cells are rapidly quantifiable by flow cytometry. Analysis of genomic DNA from recombined FYDR cells shows that this mouse model detects gene conversions, and based on the arrangement of the integrated recombination substrate, unequal sister-chromatid exchanges and repair of collapsed replication forks are also expected to reconstitute EYFP coding sequence. The rate of spontaneous recombination in primary fibroblasts derived from adult ear tissue is 1.3 ؎ 0.1 per 10 6 cell divisions. Interestingly, the rate is Ϸ10-fold greater in fibroblasts derived from embryonic tissue. We observe an Ϸ15-fold increase in the frequency of recombinant cells in cultures of ear fibroblasts when exposed to mitomycin C, which is consistent with the ability of interstrand crosslinks to induce homologous recombination. In addition to studies of recombination in cultured primary cells, the frequency of recombinant cells present in skin was also measured by direct analysis of disaggregated cells. Thus, the FYDR mouse model can be used for studies of mitotic homologous recombination both in vitro and in vivo.H uman cells incur Ϸ10 6 base lesions per day (1), many of which inhibit DNA replication and͞or induce DNA strand breaks. Homology-directed repair provides an important strategy for preventing toxicity caused by such DNA lesions. More specifically, when the replication machinery stalls, recombination between sister chromatids can replace the damaged template with an undamaged copy (2). In addition, should a replication fork collapse to form a double-strand break (e.g., because of an encounter with a single-strand break in the template DNA), the fork can be repaired by homology-directed reinsertion of the broken end (3-5). Thus, the frequency of recombination reflects the levels of certain types of DNA damage.Repair and lesion-avoidance pathways that involve homology searching are integral to DNA replication (3-7). It is estimated that Ϸ10 double-strand breaks are formed each time the mammalian genome is replicated (3), and proteins that are essential for homologous recombination (e.g., Rad51) are also essential for life (8-10). Most of the time, sequences are aligned perfectly, and flanking sequences are not exchanged. However, misalignments may result in deletions, and exchanges between homologous chromosomes may lead to loss of heterozygosity, events that are known to promote cancer (11)(12)(13)(14).A useful approach to studying recombination is to engineer two mutant expression cassett...

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“…Several studies show an increased rate of mitotic homologous recombination between duplicated DNA segments. X-rays and other carcinogens were shown to significantly increase the reversion frequency of the pinkeyed unstable (p un ) mutation, a 70-kb internal tandem duplication of p (Schiestl et al 1994(Schiestl et al , 1997. Reversion of mutations caused by tandem duplication have also been found in yeast, Chinese hamster and human cell lines, and were drastically increased by carcinogen treatments (Schiestl et al 1988;Zhang and Jenssen 1992;Aubrecht et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Structure of Chromosomal Duplicons and their Role in Mediating Human Genomic Disorders

Ji¹,

Eichler²,

Schwartz³

et al. 2000

Genome Res.

231

158

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Chromosome-specific low-copy repeats, or duplicons, occur in multiple regions of the human genome. Homologous recombination between different duplicon copies leads to chromosomal rearrangements, such as deletions, duplications, inversions, and inverted duplications, depending on the orientation of the recombining duplicons. When such rearrangements cause dosage imbalance of a developmentally important gene(s), genetic diseases now termed genomic disorders result, at a frequency of 0.7–1/1000 births. Duplicons can have simple or very complex structures, with variation in copy number from 2 to >10 repeats, and each varying in size from a few kilobases in length to hundreds of kilobases. Analysis of the different duplicons involved in human genomic disorders identifies features that may predispose to recombination, including large size and high sequence identity between the recombining copies, putative recombination promoting features, and the presence of multiple genes/pseudogenes that may include genes expressed in germ cells. Most of the chromosome rearrangements involve duplicons near pericentromeric regions, which may relate to the propensity of such regions to accumulate duplicons. Detailed analyses of the structure, polymorphic variation, and mechanisms of recombination in genomic disorders, as well as the evolutionary origin of various duplicons will further our understanding of the structure, function, and fluidity of the human genome.

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Carcinogens induce reversion of the mouse pink-eyed unstable mutation

Cited by 75 publications

References 68 publications

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Genomic Structure of the Mouse Ap3b1 Gene in Normal and Pearl Mice

Spontaneous mitotic homologous recombination at an enhanced yellow fluorescent protein (EYFP) cDNA direct repeat in transgenic mice

Structure of Chromosomal Duplicons and their Role in Mediating Human Genomic Disorders

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