肿瘤潜在新靶标:CDK12
目前已知CDK12有三种主要功能:(1)CDK12磷酸化RNA聚合酶PoLⅡ,促进转录的延伸;(2)CDK12与RNA加工因子相互作用,调控剪接;(3)介导伴转录的RNA聚合酶Ⅱ磷酸化和mRNA 3’端加工,调节内含子的多聚腺苷化。
研究表明,敲除CDK12基因会导致其下游基因的表达沉默,包括对细胞具有重要意义的DNA损伤修复基因,比如BRCA1,ATR,FANCI和FANCD2,形成类似于“DNA损伤修复基因缺陷”的状态,导致细胞对引起DNA损伤的外在条件更为敏感。同时CDK12通过定位在核散斑体(nuclear speckles)和pre-mRNA剪切体上,调节外显子的剪接。
整体而言,CDK12主要通过调控基因组转录与表达,参与DNA损伤应答或压力应答。
CDK12基因突变在肿瘤中的分布CDK12可以调节DNA损伤修复基因在内的基因转录,当CDK12蛋白功能失活时,DNA损伤修复基因表达缺陷,易引起基因组不稳定,导致肿瘤的发生与发展。通过对TCGA数据库数据分析发现CDK12基因在各癌种中均有一定频率的突变,突变频率较高的癌种包括食管癌、子宫内膜癌和膀胱癌,突变频率在10%~15%之间。另外在胃癌、结直肠癌、胰腺癌和高级别浆液性卵巢癌中也发现较高频率的CDK12基因突变。
目前对于CDK12与肿瘤发生的具体机制并不完全明确,通过对肿瘤CDK12的热点突变分析发现,最常见的CDK12移码突变或点突变多发生于激酶结构域(2/3突变),这提示大多数的突变可能引起CDK12的激酶活性丧失,降低BRCA1和BRCA2等DNA损伤修复基因的表达,破坏同源重组修复过程[3]。
参考文献
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