人類組蛋白甲基轉化酶SMYD3在DNA修復功能上扮演的角色探討

Abstract

甲基轉化酶SMYD3高度表現在許多種類的癌症中，SMYD3藉由甲基化組蛋白或是非組蛋白的受質來調控包括染色質重組、訊息傳導和控制細胞週期等動作。由於在癌症細胞中SMYD3有不正常的高度表現，且研究已指出SMYD3過表現會促進癌症細胞增生且連結到癌症預後不良，因此在許多種類的癌症SMYD3中被認為是一個預後指標。為了研究SMYD3的新功能，我利用SMYD3進行ChIP-seq實驗，並將其結果和先前發表的微陣列晶片資料庫做比對，實驗結果顯示一群和DNA損壞反應相關的基因會受到調控。進一步研究指出SMYD3會調控另一個導致癌症的路徑，DNA修復。此調控是藉由促進許多參與在同源重組的基因之表現。缺乏SMYD3的細胞表現出對於DNA損壞壓力的高度敏感，DNA斷裂及染色體重組的程度增加、修復蛋白聚集的情形降低，這些都導致同源重組功能的損害。若是在缺乏SMYD3的細胞中外源性的表現SMYD3則可以彌補這種缺陷。此外，這個對同源重組相關基因的調控是藉由在其啟動子甲基化H3K4。這些實驗結果顯示，SMYD3除了經由已知的機制促進癌症生成，也透過調控同源重組蛋白質貢獻於維持基因體的完整性。

SET and MYND domain containing-3 (SMYD3) is a methyltransferase highly expressed in many types of cancer. SMYD3 methylates various histone and non-histone targets to regulate distinct roles in chromatin remodeling, signal transduction and cell cycle control. SMYD3 is linked to increased cell proliferation and poor prognosis in human cancers. Due to its abnormal expression in tumors, SMYD3 is considered as prognostic markers in various cancers. To explore novel functions of SMYD3, we performed ChIP-seq experiments and compared the results with previously published microarray data. A group of DNA damage response genes were called. Further study showed that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination (HR). Deficiency of SMYD3 induces DNA-damage hypersensitivity, increases levels of DNA breaks and chromosomal rearrangement, decreases levels of repair foci, and leads to impairment of homologous recombination. The complementation of exogenous SMYD3 is able to restore the defects caused by SMYD3 depletion. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters. These data imply that, besides its reported oncogenic abilities, SMYD3 may maintain genome integrity by ensuring expression levels of HR proteins to cope with the high demand of restart of stalled replication forks in cancers.