Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
Genome Biol. 2011 Dec 19;12(12):R121. doi: 10.1186/gb-2011-12-12-r121.
The BLM DNA helicase plays a vital role in maintaining genome stability. Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the molecular basis of this increase is not well understood. In addition, the effect of aging on spontaneous mutagenesis in blm mutants has not been characterized. To address this, we used a lacZ reporter system in wild-type and several mutant strains of Drosophila melanogaster to analyze mechanisms of mutagenesis throughout their lifespan.
Our data show that Drosophila lacking BLM have an elevated frequency of spontaneous genome rearrangements that increases with age. Although in normal flies most genome rearrangements occur through DNA ligase 4-dependent classical end joining, most rearrangements that accumulate during aging in blm mutants do not require DNA ligase 4, suggesting the influence of an alternative end-joining mechanism. Adult blm mutants also display reduced lifespan and ligase 4-independent enhanced tumorigenesis in mitotically active tissues.
These results suggest that Drosophila BLM suppresses error-prone alternative end-joining repair of DNA double-strand breaks that can result in genome instability and tumor formation during aging. In addition, since loss of BLM significantly affects lifespan and tumorigenesis, the data provide a link between error-prone end joining, genome rearrangements, and tumor formation in a model metazoan.
BLM DNA 解旋酶在维持基因组稳定性方面起着至关重要的作用。BLM 突变会导致布卢姆综合征，这是一种罕见的疾病，与癌症易感性和早衰有关。BLM 突变的人类和小鼠自发性突变频率增加，但这种增加的分子基础尚不清楚。此外，衰老对 blm 突变体自发性突变的影响尚未得到表征。为了解决这个问题，我们使用了野生型和几种黑腹果蝇突变株的 lacZ 报告系统，分析了它们整个生命周期中的突变机制。
我们的数据表明，缺乏 BLM 的果蝇具有较高的自发基因组重排频率，且随着年龄的增长而增加。虽然在正常果蝇中，大多数基因组重排是通过 DNA 连接酶 4 依赖性经典末端连接发生的，但在 blm 突变体中随着衰老而积累的大多数重排并不需要 DNA 连接酶 4，这表明存在替代末端连接机制的影响。成年 blm 突变体也表现出较短的寿命和有丝分裂活跃组织中无需 ligase 4 的增强肿瘤发生。
这些结果表明，果蝇 BLM 抑制易错的替代末端连接修复 DNA 双链断裂，这可能导致衰老过程中的基因组不稳定和肿瘤形成。此外，由于 BLM 的缺失会显著影响寿命和肿瘤发生，因此这些数据为模型后生动物中易错末端连接、基因组重排和肿瘤形成之间提供了联系。
