KMT2C-deficient tumors have elevated APOBEC mutagenesis and genomic instability in multiple cancers.
KMT2C-deficient tumors have elevated APOBEC mutagenesis and genomic instability in multiple cancers.
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作者：
组蛋白甲基转移酶KMT2C是癌症中最常发生突变的表观遗传修饰基因之一，在mre11依赖性DNA复制叉重启中起重要作用。然而，KMT2C缺乏对肿瘤发生过程中基因组不稳定性的影响尚不清楚。我们分析了来自30个癌症队列的9663个肿瘤，报告了KMT2C突变肿瘤在几种癌症类型中具有显著过量的APOBEC突变特征。我们发现KMT2C缺陷促进APOBEC表达和脱氨酶活性，降低DNA复制速度并延迟叉的重启，促进APOBEC针对停滞叉附近单链DNA的突变。apobecc介导的突变主要在早期复制过程中积累，并倾向于沿着基因组和三维核结构域聚集。KMT2C突变肿瘤中过量的APOBEC突变特征与基因组维持缺陷升高和同源重组缺陷特征相关。我们提出KMT2C缺陷可能是APOBEC突变的启动子，在多种癌症类型的肿瘤进展过程中，它会促进进一步的基因组不稳定。kmt2c缺陷可能是复制应激和APOBEC突变的启动子，在多种癌症类型的肿瘤进展过程中导致基因组不稳定。
The histone methyltransferase KMT2C is among the most frequently mutated epigenetic modifier genes in cancer and plays an essential role in MRE11-dependent DNA replication fork restart. However, the effects of KMT2C deficiency on genomic instability during tumorigenesis are unclear. Analyzing 9,663 tumors from 30 cancer cohorts, we report that KMT2C mutant tumors have a significant excess of APOBEC mutational signatures in several cancer types. We show that KMT2C deficiency promotes APOBEC expression and deaminase activity, and compromises DNA replication speed and delays fork restart, facilitating APOBEC mutagenesis targeting single stranded DNA near stalled forks. APOBEC-mediated mutations primarily accumulate during early replication and tend to cluster along the genome and also in 3D nuclear domains. Excessive APOBEC mutational signatures in KMT2C mutant tumors correlate with elevated genome maintenance defects and signatures of homologous recombination deficiency. We propose that KMT2C deficiency is a likely promoter of APOBEC mutagenesis, which fosters further genomic instability during tumor progression in multiple cancer types. KMT2C-deficiency is a likely promoter of replication stress and APOBEC mutagenesis, which lead to genomic instability during tumor progression in multiple cancer types.
影响因子：
2.7
作者：
Shimizu A;Fujimori H;Minakawa Y;Matsuno Y;Hyodo M;Murakami Y;Yoshioka KI
通讯作者：
Yoshioka KI