APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast.
APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast.
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DOI：
10.1016/j.dnarep.2017.03.003
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发表时间：
2017-05
期刊：
影响因子：
3.8
通讯作者：
Gordenin DA
中科院分区：
文献类型：
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作者：
Saini N;Roberts SA;Sterling JF;Malc EP;Mieczkowski PA;Gordenin DA
在模式生物和癌症中已经证明了整个基因组的突变率变化。这种现象在很大程度上是由不同诱变剂的损伤特异性和给定基因组背景下DNA修复效率的差异所驱动的。在这里，我们证明了单链dna特异性胞苷脱氨酶APOBEC3B （A3B）在出芽酵母中破坏tRNA基因的效率比其他非tRNA基因组区域高1000倍。我们发现，a3b诱导的tRNA基因病变主要位于非转录链上，而在蛋白质编码基因中没有观察到转录链的偏倚。此外，RNaseH表达完全消失的细胞中tRNA基因突变加剧（Δrnh1Δrnh35）。这些数据表明a3b诱导的tRNA基因高突变存在转录依赖机制。有趣的是，在精通DNA修复的菌株中，只有1%的a3b脱氨胞嘧啶切除后形成的基本位点没有修复，导致tRNA基因突变，而18%的这些损伤在基因组的其余部分未能修复。发现a3b诱导的tRNA基因突变被碱基切除修复（BER）和无差错DNA损伤旁路通路的冗余活性有效抑制。另一方面，BER的缺乏对蛋白质编码基因的报告基因CAN1的a3b诱导突变没有深刻的影响。我们假设，tRNA基因和其他基因组位点上ssDNA形成机制的差异是修复途径选择的关键决定因素，从而影响了这些区域DNA损伤修复的效率。总的来说，我们的结果表明tRNA基因对ssdna特异性DNA损伤剂高度敏感。然而，增加tRNA基因的DNA修复功效可以防止它们的超突变，并维持基因组和蛋白质组的稳态。
Variations in mutation rates across the genome have been demonstrated both in model organisms and in cancers. This phenomenon is largely driven by the damage specificity of diverse mutagens and the differences in DNA repair efficiency in given genomic contexts. Here, we demonstrate that the single-strand DNA-specific cytidine deaminase APOBEC3B (A3B) damages tRNA genes at a 1000-fold higher efficiency than other non-tRNA genomic regions in budding yeast. We found that A3B-induced lesions in tRNA genes were predominantly located on the non-transcribed strand, while no transcriptional strand bias was observed in protein coding genes. Furthermore, tRNA gene mutations were exacerbated in cells where RNaseH expression was completely abolished (Δrnh1Δrnh35). These data suggest a transcription-dependent mechanism for A3B-induced tRNA gene hypermutation. Interestingly, in strains proficient in DNA repair, only 1% of the abasic sites formed upon excision of A3B-deaminated cytosines were not repaired leading to mutations in tRNA genes, while 18% of these lesions failed to be repaired in the remainder of the genome. A3B-induced mutagenesis in tRNA genes was found to be efficiently suppressed by the redundant activities of both base excision repair (BER) and the error-free DNA damage bypass pathway. On the other hand, deficiencies in BER did not have a profound effect on A3B-induced mutations in CAN1, the reporter for protein coding genes. We hypothesize that differences in the mechanisms underlying ssDNA formation at tRNA genes and other genomic loci are the key determinants of the choice of the repair pathways and consequently the efficiency of DNA damage repair in these regions. Overall, our results indicate that tRNA genes are highly susceptible to ssDNA-specific DNA damaging agents. However, increased DNA repair efficacy in tRNA genes can prevent their hypermutation and maintain both genome and proteome homeostasis.
NMD的失活增加了酿酒酵母中Sup45废话突变体的生存能力。
影响因子：
--
作者：
Chabelskaya, Svetlana;Gryzina, Valentina;Moskalenko, Svetlana;Le Goff, Catherine;Zhouravleva, Galina
通讯作者：
Zhouravleva, Galina