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Nature:癌症治疗新策略——以己之矛攻己之盾

来源:生物谷 2015-07-27 10:25

                                                                    

2015年7月27日讯  /生物谷BIOON/  --近日,来自英国牛津大学的一个研究小组在著名国际学术期刊nature发文,他们在研究细胞如何重复利用合成DNA的"砖块"--核苷酸的过程中,发现了一种治疗癌症的潜在治疗方法。
 
DNA复制和DNA损伤修复过程都需要以核苷酸为合成原料,细胞除了通过从头合成途径获得核苷酸,还会对来自死亡细胞的核苷酸或通过饮食消化得到的核苷酸进行重复利用。回收利用的核苷酸来源复杂,经常会包含各种表观遗传修饰,但DNA复制过程中DNA甲基化的表观遗传性主要来自于亲本DNA链上携带的甲基化修饰,如果在复制过程中随机插入一些携带修饰碱基的核苷酸,可能会对表观基因组的保真性造成重大影响,可导致细胞发生癌变或死亡。但细胞究竟如何防止携带表观修饰的碱基插入到新合成DNA仍是一个未解之谜。
 
在这项研究中,研究人员发现进行核苷酸回收的酶具有非常高的特异性,它们不会使用携带修饰的核苷酸,从而保证新合成的DNA在表观遗传修饰上保持"干净"。当研究人员利用5hmdC修饰碱基对不同癌细胞系进行暴露处理,结果发现5hmdC会导致一些癌细胞系发生致死。
 
随后研究人员利用基因组学方法发现对5hmdC具有易感性的癌细胞系都会过表达胞嘧啶脱氨酶(CDA),这种酶能够将5hmdC或5fdC转化为尿嘧啶的不同修饰形式插入到DNA中,导致DNA损伤累积,最终诱发细胞死亡。
 
总的来说,这项研究发现细胞在回收核苷酸的过程中会通过一系列高特异性的酶对携带修饰的核苷酸进行筛选,防止其插入到DNA,而一些特定类型的癌细胞中会过表达CDA,累积DNA损伤导致细胞死亡,因此利用这一过程或可开发新的癌症治疗药物,对于癌症治疗具有重要提示意义。(生物谷Bioon.com)
 
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CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer
 
Melania Zauri Georgina Berridge Marie-La?titia Thézénas Kathryn M. Pugh Robert Goldin Benedikt M. Kessler Skirmantas Kriaucionis
 
Cells require nucleotides to support DNA replication and repair damaged DNA. In addition to de novo synthesis, cells recycle nucleotides from the DNA of dying cells or from cellular material ingested through the diet. Salvaged nucleosides come with the complication that they can contain epigenetic modifications. Because epigenetic inheritance of DNA methylation mainly relies on copying of the modification pattern from parental strands1, 2, 3, random incorporation of pre-modified bases during replication could have profound implications for epigenome fidelity and yield adverse cellular phenotypes. Although the salvage mechanism of 5-methyl-2′deoxycytidine (5mdC) has been investigated before4, 5, 6, it remains unknown how cells deal with the recently identified oxidized forms of 5mdC: 5-hydroxymethyl-2′deoxycytidine (5hmdC), 5-formy-2′deoxycytidine (5fdC) and 5-carboxyl-2′deoxycytidine (5cadC)7, 8, 9, 10. Here we show that enzymes of the nucleotide salvage pathway display substrate selectivity, effectively protecting newly synthesized DNA from the incorporation of epigenetically modified forms of cytosine. Thus, cell lines and animals can tolerate high doses of these modified cytidines without any deleterious effects on physiology. Notably, by screening cancer cell lines for growth defects after exposure to 5hmdC, we unexpectedly identify a subset of cell lines in which 5hmdC or 5fdC administration leads to cell lethality. Using genomic approaches, we show that the susceptible cell lines overexpress cytidine deaminase (CDA). CDA converts 5hmdC and 5fdC into variants of uridine that are incorporated into DNA, resulting in accumulation of DNA damage, and ultimately, cell death. Our observations extend current knowledge of the nucleotide salvage pathway by revealing the metabolism of oxidized epigenetic bases, and suggest a new therapeutic option for cancers, such as pancreatic cancer, that have CDA overexpression and are resistant to treatment with other cytidine analogues11.
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