Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, Tennessee.
Cancer Res. 2019 Apr 1;79(7):1612-1623. doi: 10.1158/0008-5472.CAN-18-2705. Epub 2019 Jan 4.
The cellular DNA replication stress response functions to stabilize DNA replication forks and inhibits genome instability and tumorigenesis induced by oncogenes. However, the specific proteins required for resolving oncogenic stress remain poorly understood. Here we report that Smarcal1 and Zranb3, closely related replication fork-remodeling proteins, have nonredundant functions in resolving Myc-induced DNA replication stress. In Myc-overexpressing primary cells, significant differences in replication fork stalling, collapse, and DNA damage were detected between cells deficient in Smarcal1 or Zranb3, leading to changes in proliferation and apoptosis. These differences were also reflected in Myc-induced lymphoma development; haploinsufficiency of Smarcal1 resulted in accelerated lymphomagenesis, whereas haploinsufficiency of Zranb3 inhibited lymphoma development. Complete loss of either protein resulted in disparate survival outcomes. Our results reveal that endogenous replication stress from Myc in primary cells requires both alleles of and and demonstrate the requirement of both proteins to stabilize replication forks upon Myc dysregulation in a nonredundant manner. SIGNIFICANCE: Smarcal1 and Zranb3 are essential, but nonredundant, for responding to DNA replication stress and stabilizing replication forks following Myc overexpression..
细胞 DNA 复制应激反应的功能是稳定 DNA 复制叉，抑制致癌基因诱导的基因组不稳定性和肿瘤发生。然而，解析致癌应激所需的特定蛋白质仍知之甚少。在这里，我们报告 Smarcal1 和 Zranb3 这两种密切相关的复制叉重塑蛋白在解析 Myc 诱导的 DNA 复制应激方面具有非冗余功能。在 Myc 过表达的原代细胞中，在 Smarcal1 或 Zranb3 缺失的细胞中，复制叉停滞、崩溃和 DNA 损伤存在显著差异，导致增殖和凋亡发生变化。这些差异也反映在 Myc 诱导的淋巴瘤发展中；Smarcal1 的单倍不足导致淋巴瘤发生加速，而 Zranb3 的单倍不足抑制淋巴瘤发展。两种蛋白质的完全缺失导致不同的存活结果。我们的结果表明，原代细胞中 Myc 引起的内源性复制应激需要 Smarcal1 和 Zranb3 的两个等位基因，并证明在 Myc 失调时，这两种蛋白质以非冗余的方式稳定复制叉是必需的。意义：Smarcal1 和 Zranb3 是应对 DNA 复制应激和稳定 Myc 过表达后复制叉所必需的，但不是冗余的。
