Analysis of wild-type and mutant SL3-3 murine leukemia virus insertions in the c-myc promoter during lymphomagenesis reveals target site hot spots, virus-dependent patterns, and frequent error-prone gap repair
Analysis of wild-type and mutant SL3-3 murine leukemia virus insertions in the c-myc promoter during lymphomagenesis reveals target site hot spots, virus-dependent patterns, and frequent error-prone gap repair
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DOI：
10.1128/jvi.79.1.67-78.2005
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发表时间：
2005-01-01
影响因子：
5.4
通讯作者：
Pedersen, FS
中科院分区：
文献类型：
--
作者：
Nielsen, AA;Sorensen, AB;Pedersen, FS
将小鼠白血病逆转录病毒SL3-3注入易感株的新生小鼠体内，可在造血系统的t细胞区诱发淋巴瘤。先前，我们的实验室报道了SL3-3缺失突变体比野生型病毒更快地诱导t细胞肿瘤（S. Ethelberg, a . B. Sorensen， J. Schmidt, a . Luz， F. S. Pedersen， J. Virol. 71:9796-9799, 1997）。野生型SL3-3 [SL3-3(wt)]和增强子缺失突变体诱导的淋巴瘤中c-myc原癌基因启动子区域前病毒整合的PCR分析显示，对该位点的靶向频率存在差异。我们在这里报告了SL3-3（wt）的前病毒插入到c-myc启动子区域的模式，SL3-3是更快的变体，以及来自大约250个肿瘤的其他增强子变体。该分析揭示了(i) C -myc启动子区域的几个整合位点热点，（ii） SL3-3（wt）和增强子缺失突变病毒之间的整合模式差异，（iii）肿瘤潜伏期与原病毒插入C -myc启动子的数量之间的相关性，以及（iv）一个[5'-(a /C/G)TA(C/G/T)-3']整合位点共识序列。出乎意料的是，大约12%的测序插入与原病毒侧翼的直接重复序列中的点突变有关。基于这些结果，我们提出了一个容易出错的宿主-原病毒连接间隙修复模型。
The murine leukemia retrovirus SL3-3 induces lymphomas in the T-cell compartment of the hematopoetic system when it is injected into newborn mice of susceptible strains. Previously, our laboratory reported on a deletion mutant of SL3-3 that induces T-cell tumors faster than the wild-type virus (S. Ethelberg, A. B. Sorensen, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:9796-9799, 1997). PCR analyses of proviral integrations in the promoter region of the c-myc proto-oncogene in lymphomas induced by wild-type SL3-3 [SL3-3(wt)] and the enhancer deletion mutant displayed a difference in targeting frequency into this locus. We here report on patterns of proviral insertions into the c-myc promoter region from SL3-3(wt), the faster variant, as well as other enhancer variants from a total of approximately 250 tumors. The analysis reveals (i) several integration site hot spots in the c-myc promoter region, (ii) differences in integration patterns between SL3-3(wt) and enhancer deletion mutant viruses, (iii) a correlation between tumor latency and the number of proviral insertions into the c-myc promoter, and (iv) a [5'-(A/C/G)TA(C/G/T)-3'] integration site consensus sequence. Unexpectedly, about 12% of the sequenced insertions were associated with point mutations in the direct repeat flanking the provirus. Based on these results, we propose a model for error-prone gap repair of host-provirus junctions.