Hu Xiaoju, Biswas Antara, De Subhajyoti
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ 08901, USA.
NAR Cancer. 2022 Jul 25;4(3):zcac023. doi: 10.1093/narcan/zcac023. eCollection 2022 Sep.
The histone methyltransferase 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 deficiency on genomic instability during tumorigenesis are unclear. Analyzing 9,663 tumors from 30 cancer cohorts, we report that mutant tumors have a significant excess of APOBEC mutational signatures in several cancer types. We show that 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 mutant tumors correlate with elevated genome maintenance defects and signatures of homologous recombination deficiency. We propose that deficiency is a likely promoter of APOBEC mutagenesis, which fosters further genomic instability during tumor progression in multiple cancer types.
组蛋白甲基转移酶是癌症中最常发生突变的表观遗传修饰基因之一，在依赖MRE11的DNA复制叉重启过程中发挥着重要作用。然而，其缺陷在肿瘤发生过程中对基因组不稳定性的影响尚不清楚。通过分析来自30个癌症队列的9663个肿瘤，我们发现该突变肿瘤在几种癌症类型中显著存在过量的载脂蛋白B mRNA编辑酶催化多肽（APOBEC）突变特征。我们表明，该缺陷会促进APOBEC表达和脱氨酶活性，损害DNA复制速度并延迟复制叉重启，从而促进APOBEC对停滞复制叉附近单链DNA的诱变作用。APOBEC介导的突变主要在早期复制过程中积累，并倾向于沿基因组聚集，也在三维核结构域中聚集。该突变肿瘤中过量的APOBEC突变特征与基因组维持缺陷增加和同源重组缺陷特征相关。我们提出，该缺陷可能是APOBEC诱变作用的促进因素，在多种癌症类型的肿瘤进展过程中进一步促进基因组不稳定性。
