Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Molecular Biosciences, LIVESTRONG Cancer Institute of the Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA.
Cell. 2019 Jan 10;176(1-2):127-143.e24. doi: 10.1016/j.cell.2018.12.008.
DNA damage provokes mutations and cancer and results from external carcinogens or endogenous cellular processes. However, the intrinsic instigators of endogenous DNA damage are poorly understood. Here, we identify proteins that promote endogenous DNA damage when overproduced: the DNA "damage-up" proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six function clusters, demonstrating DDP mechanisms in three: reactive oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their RNAs in tumors predict heavy mutagenesis and a poor prognosis. Half of the tested human homologs promote DNA damage and mutation when overproduced in human cells, with DNA damage-elevating mechanisms like those in E. coli. Our work identifies networks of DDPs that provoke endogenous DNA damage and may reveal DNA damage-associated functions of many human known and newly implicated cancer-promoting proteins.
DNA 损伤会引发突变和癌症，其原因来自外部致癌物质或内源性细胞过程。然而，内源性 DNA 损伤的内在引发因素还不太清楚。在这里，我们鉴定出了在过量产生时会促进内源性 DNA 损伤的蛋白质：DNA“损伤诱导”蛋白（DDP）。我们在大肠杆菌中发现了一个庞大的 DDP 网络，并将其分解为六个功能群，展示了其中三个的 DDP 机制：跨膜转运蛋白导致活性氧增加、复制酶结合导致染色体丢失以及转录因子导致复制停滞。它们的 284 个人类同源物在已知的癌症驱动基因中过度表达，其在肿瘤中的 RNA 预测会导致大量突变和预后不良。在人类细胞中过量产生时，测试的人类同源物中有一半会促进 DNA 损伤和突变，其 DNA 损伤升高的机制与大肠杆菌中的类似。我们的工作鉴定出了引发内源性 DNA 损伤的 DDP 网络，这可能揭示了许多已知和新发现的促进癌症的人类蛋白与 DNA 损伤相关的功能。
