Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Hadassah Human Embryonic Stem Cell Research Center, Goldyne Savad Institute of Gene Therapy, Hadassah- Hebrew University Medical Center, Jerusalem, Israel.
Cancer Res. 2015 Jul 1;75(13):2663-73. doi: 10.1158/0008-5472.CAN-14-3635. Epub 2015 May 14.
The DNA damage response (DDR) is a comprehensive and complex network of phosphorylation-mediated signaling pathways that originates endogenously from the DNA lesion and activates intrinsic DNA repair mechanisms. Here we describe a macrophage-dependent mechanism that regulates the response to DNA damage. We demonstrate that human monocytes, by releasing macrophage-derived HB-EGF, enhance DDR in neighboring cells suffering from DNA damage. Consequently, HB-EGF-treated cells exhibit higher double-strand break (DSB) rejoining and display lower levels of residual DSBs. Diethylnitrosamine (DEN) injection induce DSBs along with elevation in the number of macrophages and HB-EGF expression. Significantly, macrophage depletion or blocking HB-EGF activity results in higher levels of nonrepairable DSBs, suggesting that macrophages play a role in the resolution of DNA damage via HB-EGF. This study establishes that macrophages, acting through the activation of the EGFR cascade, constitute an important cell nonautonomous physiologic component of the DDR and points to a unique role played by immune cells in maintaining genome integrity.
DNA 损伤反应 (DDR) 是一个综合而复杂的磷酸化介导的信号通路网络，它源自内源性的 DNA 损伤，并激活内在的 DNA 修复机制。在这里，我们描述了一种巨噬细胞依赖性的机制，该机制调节对 DNA 损伤的反应。我们证明，人类单核细胞通过释放巨噬细胞衍生的 HB-EGF，增强了遭受 DNA 损伤的邻近细胞的 DDR。因此，HB-EGF 处理的细胞表现出更高的双链断裂 (DSB) 重连，并显示出更低水平的残余 DSB。二乙基亚硝胺 (DEN) 注射会导致 DSB 的形成，同时伴随着巨噬细胞数量的增加和 HB-EGF 表达的增加。重要的是，巨噬细胞耗竭或阻断 HB-EGF 活性会导致更多不可修复的 DSB，这表明巨噬细胞通过 HB-EGF 在 DNA 损伤的修复中发挥作用。这项研究确立了巨噬细胞通过激活 EGFR 级联反应，构成了 DDR 的一个重要的非自主性生理组成部分，并指出免疫细胞在维持基因组完整性方面发挥了独特的作用。
