کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1980724 1061876 2010 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Small scale genetic alterations contribute to increased mutability at the X-linked Hprt locus in vivo in Blm hypomorphic mice
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Small scale genetic alterations contribute to increased mutability at the X-linked Hprt locus in vivo in Blm hypomorphic mice
چکیده انگلیسی

BLM, the gene mutated in Bloom syndrome (BS), encodes an ATP-dependent RecQ DNA helicase that is involved in the resolution of Holliday junctions, in the suppression of crossovers and in the management of damaged replication forks. Cells from BS patients have a characteristically high level of sister chromatid exchanges (SCEs), and increased chromosomal aberrations. Fibroblasts and lymphocytes of BS patients also exhibit increased mutation frequency at the X-linked reporter gene HPRT, suggesting that BLM also plays a role in preventing small scale genomic rearrangements. However, the nature of such small scale alterations has not been well characterized. Here we report the characterization of Hprt mutations in vivo in Blm hypomorphic mice, Blmtm1Ches/Blmtm3Brd. We found that the frequency of Hprt mutants was increased about 6-fold in the Blmtm1Ches/Blmtm3Brd mice when compared to Blmtm3Brd heterozygous mice or wildtype mice. Molecular characterization of Hprt gene in the mutant clones indicates that many of the mutations were caused by deletions that range from several base pairs to several thousand base pairs. While deletions in BLM-proficient somatic cells are often shown to be mediated by direct repeats, all three deletion junctions in Hprt of Blmtm1Ches/Blmtm3Brd mice were flanked by inverted repeats, suggesting that secondary structures formed during DNA replication, when resolved improperly, may lead to deletions. In addition, single base pair substitution and insertion/deletion were also detected in the mutant clones. Taken together, our results indicated that BLM function is important in preventing small scale genetic alterations. Thus, both large scale and small scale genetic alterations are elevated when BLM is reduced, which may contribute to loss of function of tumor suppressor genes and subsequent tumorigenesis.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: DNA Repair - Volume 9, Issue 5, 4 May 2010, Pages 551–557
نویسندگان
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