Wang Luo, Wang Jie, Sun Shiyong, Rodriguez Marivonne, Yue Ping, Jang Se Jin, Mao Li
Molecular Biology Laboratory, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Int J Oncol. 2006 Jul;29(1):201-7.
De novo promoter DNA methylation represses gene transcription and is a common mechanism to inactivate tumor suppressor genes in tumorigenesis. DNMT3B plays an important role in de novo DNA methylation. We report here the identification of a novel DNMT3B subfamily, termed DeltaDNMT3B, whose expression is initiated through a promoter located at intron 4 and exon 5 of the DNMT3B gene. At least 7 transcriptional variants of DeltaDNMT3B have been observed as the result of alternative pre-mRNA splicing. Predicted proteins derived from these variants suggest that 4 of the variants share a conservative enzymatic domain but contain a variable PWWP motif, a putative DNA binding structure, whereas 3 of the variants lack the enzymatic domain due to predicted premature translational termination. In non-small cell lung cancer (NSCLC) cell lines, DeltaDNMT3B variants are frequently expressed and are the predominant forms of DNMT3B. Similarly, DeltaDNMT3B variants are frequently expressed in primary NSCLC but are not detectable or are expressed at low levels in corresponding normal lung tissue. Our results indicate that DeltaDNMT3B is the major expression form of DNMT3B in NSCLC and may play an important role in the development of aberrant promoter methylation during lung tumorigenesis.
从头开始的启动子DNA甲基化会抑制基因转录，是肿瘤发生过程中使肿瘤抑制基因失活的常见机制。DNMT3B在从头开始的DNA甲基化中起重要作用。我们在此报告鉴定出一个新的DNMT3B亚家族，称为DeltaDNMT3B，其表达通过位于DNMT3B基因第4内含子和第5外显子的启动子起始。由于选择性前体mRNA剪接，已观察到DeltaDNMT3B至少有7种转录变体。从这些变体衍生的预测蛋白质表明，其中4种变体共享一个保守的酶结构域，但含有可变的PWWP基序，这是一个推定的DNA结合结构，而其中3种变体由于预测的过早翻译终止而缺乏酶结构域。在非小细胞肺癌（NSCLC）细胞系中，DeltaDNMT3B变体经常表达，并且是DNMT3B的主要形式。同样，DeltaDNMT3B变体在原发性NSCLC中经常表达，但在相应的正常肺组织中无法检测到或表达水平较低。我们的结果表明，DeltaDNMT3B是NSCLC中DNMT3B的主要表达形式，可能在肺肿瘤发生过程中异常启动子甲基化的发展中起重要作用。
