DNA Repair in <i>Drosophila</i>

Sekelsky, Jeff; Brodsky, Michael; Burtis, Kenneth C.

doi:10.1083/jcb.150.2.f31

Cited by 122 publications

(50 citation statements)

References 48 publications

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“…Even if the true phylogeny of these elements was not star-like, any departure from recombination areas of euchromatin (Figure 3). There-fore, it does appear that there is a substitutional bias toward (De Cock et al 1992;Van Der Helm et al 1997;Sekelsky et al 2000). G and C associated with recombination on the autosomes.…”

Section: ; Hey and Kliman 2002)mentioning

confidence: 99%

Genomic Heterogeneity of Background Substitutional Patterns in Drosophila melanogaster

2005

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Mutation is the underlying force that provides the variation upon which evolutionary forces can act. It is important to understand how mutation rates vary within genomes and how the probabilities of fixation of new mutations vary as well. If substitutional processes across the genome are heterogeneous, then examining patterns of coding sequence evolution without taking these underlying variations into account may be misleading. Here we present the first rigorous test of substitution rate heterogeneity in the Drosophila melanogaster genome using almost 1500 nonfunctional fragments of the transposable element DNAREP1_DM. Not only do our analyses suggest that substitutional patterns in heterochromatic and euchromatic sequences are different, but also they provide support in favor of a recombination-associated substitutional bias toward G and C in this species. The magnitude of this bias is entirely sufficient to explain recombination-associated patterns of codon usage on the autosomes of the D. melanogaster genome. We also document a bias toward lower GC content in the pattern of small insertions and deletions (indels). In addition, the GC content of noncoding DNA in Drosophila is higher than would be predicted on the basis of the pattern of nucleotide substitutions and small indels. However, we argue that the fast turnover of noncoding sequences in Drosophila makes it difficult to assess the importance of the GC biases in nucleotide substitutions and small indels in shaping the base composition of noncoding sequences.M UTATION is the substrate of evolution; it creates by selective forces specific to their functional capacity. In the variation upon which evolutionary forces will some cases, such selective effects are well known, such as ultimately act. With every novel mutation there is an those related to maintenance of the integrity of proteinassociated probability of fixation, which may be affected coding sequences, but many other, possibly more subtle, by neutral forces, such as random genetic drift or biased patterns are likely yet to be discovered. gene conversion, or selective forces. Both mutation ratesIn this context, the study of the background patterns and fixation probabilities of new mutations may vary of substitution not only is interesting in its own right, but across the genome, which may play a role in generating also should help us rigorously define null hypotheses patterns of extant sequence variation. One of the goals against which we can compare patterns of substitution of genomic biology is to understand how heterogeneity found in functional sequences such as genes. This, in in evolutionary forces such as mutation, drift, biased gene turn, should help us identify selective forces that act conversion, and selection can actively shape genome sewithin genes and thereby understand which genic feaquences and structure.tures are of functional significance. The evolution of both functional and nonfunctional seIn this genomic age, the need for careful quantificaquences might be modulated by an...

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Section: ; Hey and Kliman 2002)mentioning

confidence: 99%

Genomic Heterogeneity of Background Substitutional Patterns in Drosophila melanogaster

2005

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“…Alternatively, DmBlm may not be absolutely required to unwind the D-loop. There are two other RecQ helicases in Drosophila, RecQ5 and RecQ4 (27), and it is possible that one of these or some other helicase can weakly compensate for loss of DmBlm. In either scenario, a model in which multiple rounds of invasion, synthesis, and dissociation are required to repair across a large gap predicts that in mus309 mutants, dissociation will ultimately fail.…”

Section: Flanking Deletions Are Not Caused By a Lack Of Repair Synthesismentioning

confidence: 99%

Formation of deletions during double-strand break repair in Drosophila DmBlm mutants occurs after strand invasion

McVey

LaRocque

Adams

et al. 2004

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

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The importance of this family is highlighted by the observation that mutations in three of the five human RecQ helicases, WRN, BLM, and RECQ4, cause the Werner, Bloom, and RothmundThomson syndromes, respectively (2-4). These three rare disorders are characterized by genomic instability and cancer predisposition, and patients with Werner and RothmundThomson syndromes also display symptoms of premature aging.Bloom syndrome (BS) patients develop a wide spectrum of cancers typical of those found in older individuals of the general population, including sarcomas, lymphomas, and epithelial cancers (reviewed in ref. 5). A hallmark of BS cells is a large increase in sister chromatid exchanges (6). In addition, BS cells show elevated levels of chromosome breaks, rearrangements, and deletions (7). Both in vivo and in vitro experiments with broken plasmids demonstrate that repair of double-strand breaks (DSBs) in the absence of BLM results in products with large deletions (8, 9). Therefore, a clearer understanding of the underlying events that cause chromosomal deletions in BS cells may provide insight into how the BLM protein prevents cancer in normal cells.Accumulating evidence suggests that the BLM protein functions in homologous recombination repair pathways to promote genomic stability. In humans, BLM interacts with RAD51, a protein required for the strand invasion step that initiates DSB repair by homologous recombination (10). Sgs1p, the Saccharomyces cerevisiae homologue of BLM, also interacts with Rad51p (10), and sgs1 mutants have an increased rate of chromosomal rearrangements such as translocations and deletions. Interestingly, Sgs1p suppresses recombination between DNA sequences with imperfect homology (11), consistent with the notion that it functions both to promote accurate recombination and to suppress inappropriate recombination.In vitro experiments provide further evidence that BLM functions during recombination. The human BLM helicase preferentially unwinds Holliday junctions, branched DNA structures, and other homologous recombination intermediates (12)(13)(14). Interestingly, BLM has also been shown to be adept at binding to and unwinding D-loops (15), which are thought to be the initial intermediate in DSB repair by homologous recombination.The Drosophila melanogaster ortholog of BLM, DmBlm, is encoded by the mus309 gene (16). Mutations in mus309 cause increased sensitivity to ionizing radiation and defects in DSB repair. Reminiscent of the human phenotype, deletions flanking a DSB site on a plasmid are frequently observed in mus309 mutants (17, 18). We recently used a chromosomal DSB repair assay to demonstrate that mus309 mutants are defective in the repair of double-strand gaps created by the excision of a P transposable element (19). Double-strand gaps generated by P element excision are repaired predominantly through a homologous recombination pathway termed synthesis-dependent strand annealing (SDSA) (Fig. 1). During SDSA, single-stranded DNA is generated by 5Ј to 3Ј resection of each end. One ...

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“…In response to ionizing radiation, Drosophila 'p53', like fish p53, is not induced; however, it has been shown that Drosophila p53 is phosphorylated, and that this phosphorylation is necessary for subsequent apoptosis (Lee et al, 2003). Drosophila lack an mdm2 homolog, providing further evidence that this species does not regulate p53-like activity through protein stabilization (Sekelsky et al, 2000).…”

Section: Lack Of P53 Induction In Fish Cells By Model Chemotherapeutimentioning

confidence: 85%

Lack of p53 induction in fish cells by model chemotherapeutics

2006

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DNA Repair in Drosophila

Cited by 122 publications

References 48 publications

Genomic Heterogeneity of Background Substitutional Patterns in Drosophila melanogaster

Genomic Heterogeneity of Background Substitutional Patterns in Drosophila melanogaster

Formation of deletions during double-strand break repair in Drosophila DmBlm mutants occurs after strand invasion

Lack of p53 induction in fish cells by model chemotherapeutics

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