FHIT loss-induced DNA damage creates optimal APOBEC substrates: Insights into APOBEC-mediated mutagenesis.
FHIT loss-induced DNA damage creates optimal APOBEC substrates: Insights into APOBEC-mediated mutagenesis.
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DOI：
10.18632/oncotarget.2636
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发表时间：
2015-02-20
期刊：
影响因子：
--
通讯作者：
Huebner K
中科院分区：
文献类型：
--
作者：
Waters CE;Saldivar JC;Amin ZA;Schrock MS;Huebner K
APOBEC胞苷脱氨酶活性是癌症超突变的主要来源。但先前的研究表明，在APOBEC过表达的癌症中，没有观察到这些酶的TC上下文特征，这表明应该确定导致这种突变的协同因素。脆性组氨酸三联体蛋白(FHIT)是一种肿瘤抑制因子和DNA守护者，在50%的癌症中缺失或沉默。FHIT蛋白活性的丧失通过减少胸苷激酶1的表达，增加DNA断裂，以及正常细胞和癌细胞的全球基因组不稳定，导致复制压力。利用癌症基因组图谱(TCGA)的数据，我们发现FHIT低/APOBEC3B高表达的肺腺癌显示APOBEC特征突变的数量显著增加。该队列中FHIT表达正常的肿瘤样本没有表现出APOBEC超突变，尽管APOBEC3B表达很高。在体外，沉默FHIT表达会增加APOBEC3B诱导的TP53基因的C>；T突变。此外，通过补充胸苷抑制FHIT丢失诱导的DNA损伤，降低了FHIT-Low/APOBEC3B-High细胞中TP53突变的负担。我们得出结论，APOBEC3B过表达和FHIT-Lost诱导的DNA损伤是独立的事件，当同时发生时，会导致APOBEC诱导的突变频率显著增加，从而推动癌症进展。
APOBEC cytidine deaminase activity is a major source of hypermutation in cancer. But previous studies have shown that the TC context signature of these enzymes is not observed in sizable fractions of cancers with overexpression of APOBEC, suggesting that cooperating factors that contribute to this mutagenesis should be identified. The fragile histidine triad protein (Fhit) is a tumor suppressor and DNA caretaker that is deleted or silenced in >50% of cancers. Loss of Fhit protein activity causes replication stress through reduced Thymidine Kinase 1 expression, increased DNA breaks, and global genome instability in normal and cancer cells. Using data from The Cancer Genome Atlas (TCGA), we show that FHIT-low/APOBEC3B-high expressing lung adenocarcinomas display significantly increased numbers of APOBEC signature mutations. Tumor samples in this cohort with normal FHIT expression do not exhibit APOBEC hypermutation, despite having high APOBEC3B expression. In vitro, silencing Fhit expression elevates APOBEC3B-directed C > T mutations in the TP53 gene. Furthermore, inhibition of Fhit loss-induced DNA damage via thymidine supplementation decreases the TP53 mutation burden in FHIT-low/APOBEC3B-high cells. We conclude that APOBEC3B overexpression and Fhit-loss induced DNA damage are independent events that, when occurring together, result in a significantly increased frequency of APOBEC-induced mutations that drive cancer progression.
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