Drosha
Drosha是一种RNA酶III[5]，在人类基因组中由5号染色体上的DROSHA基因（旧称RNASEN）编码[6][7][8]，于2000年被克隆发表，最初被发现为切割rRNA前驱物（pre-rRNA）的一种RNA酶[9]，现已知其主要功能为在miRNA生成的初期切割miRNA的前驱物，此蛋白可与DGCR8蛋白组成微加工复合体[10]，将DNA转录产生的pri-miRNA切割成长约70nt的pre-miRNA，后者可再由Dicer切割产生成熟的miRNA[11]。Drosha、Dicer与其他参与miRNA生成的蛋白之表现量与某些癌症相关[12]。
功能[编辑]
RNA酶III皆为切割双股RNA的RNA内切酶，其中Drosha在细胞核中参与miRNA前驱物切割的初始步骤[8][11]。miRNA的生成过程最初是由RNA聚合酶II转录产生可长达数kb、具5′端帽与多腺苷酸尾的初级转录本pri-miRNA（初级miRNA）[13][14]，其受Drosha切割后会形成长约70nt、且3′端具2个突出碱基（overhang）的pre-miRNA（前miRNA）。pre-miRNA可与XPO5蛋白结合，由细胞核被送入细胞质中，其3′端的突出碱基可被另一种RNA酶IIIDicer所识别，后者可再将pre-miRNA切割成长22nt的双股RNA，其中的一股即是成熟的miRNA，可与RNA诱导沉默复合体（RISC）结合而进行RNA干扰，切割目标mRNA或抑制其翻译以达成基因静默的效果[15]。
Drosha切割pri-miRNA时会与两个RNA结合蛋白DGCR8共同组成称为微加工复合体的蛋白三聚体[16][17][18][19]，DGCR8在模式生物黑腹果蝇与秀丽隐杆线虫中称为Pasha，即“Drosha的伙伴蛋白”（partner of Drosha）之简称[20]，Drosha需在与DGCR8结合的情况下才能进行切割[21]。除必要的Drosha与DGCR8外，微加工复合体还可能包含EWSR1、异质核糖核蛋白、FUS与DEAD-BoxRNA解旋酶（p68、p72）等其他蛋白以帮助切割pri-miRNA[22][23]，有些种类的pri-miRNA只有在特定辅助蛋白存在时才能被Drosha切割[24]。
Drosha大多位于细胞核中，但也有些Drosha不含核定位序列（NLS）而位于细胞质中，称为c-Drosha，可能以其他机制调控基因表达[25][26]。另外Drosha与Dicer也参与DNA修补[27]。
少数miRNA以非典型的方式生成，不需经Drosha切割，此类miRNA称为Mirtron，编码序列位于其他基因的内含子中，可随该基因的mRNA转录后进行剪接时被切割形成pre-miRNA，因此不需依赖Drosha[28]；此外，还有些miRNA（simtron）前驱物的切割仰赖Drosha，但不需DGCR8、XPO5与Dicer[29]。
临床意义[编辑]
Drosha等参与miRNA生成的蛋白表现量与某些癌症相关[12]，例如某些种类的乳癌病患的Drosha与Dicer的表现量下降[30]，癌症基因组图谱中也显示数种乳癌、大肠癌与食管癌病患细胞质中的Drosha（即c-Drosha）表现量增加[25]。
参考文献[编辑]
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