The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response.
The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response.
复制标题
推定的肿瘤抑制剂昼夜节律基因NPAS2参与了DNA损伤反应。
DOI：
10.1158/1541-7786.mcr-07-2094
复制
发表时间：
2008-09
影响因子：
5.2
通讯作者：
Zhu, Yong
中科院分区：
文献类型：
--
作者：
Hoffman, Aaron E.;Zheng, Tongzhang;Ba, Yue;Zhu, Yong
除了调节睡眠和觉醒之外，昼夜节律系统可能在其他生物过程中发挥重要作用，包括与肿瘤发生有关的途径。我们实验室最近进行的两项遗传关联研究表明，神经元 PAS 结构域蛋白 2 (NPAS2)（一种核心昼夜节律基因和转录调节因子）的错义突变与乳腺癌和非霍奇金淋巴瘤的风险显着相关。我们目前的功能分析提供了第一个体外证据，进一步证明RNA干扰介导的NPAS2耗竭的细胞未能表现出响应诱变剂治疗的预期细胞周期延迟。通过彗星试验测得的 DNA 修复能力也受到损害。此外，基于通路的 PCR 表达阵列对 DNA 损伤信号重要的基因表明，NPAS2 的敲除可显着抑制多个细胞周期和 DNA 修复基因的表达。因此，NPAS2可能通过影响癌症相关基因的表达在肿瘤发生中发挥作用，并且可以被认为是一种新型的肿瘤抑制因子。
Apart from regulating sleep and wakefulness, the circadian system may play an important role in other biological processes, including pathways involved in tumorigenesis. Two genetic association studies recently conducted by our lab have demonstrated that a missense mutation in neuronal PAS domain protein 2 (NPAS2), a core circadian gene and transcriptional regulator, is significantly associated with risk of breast cancer and non-Hodgkin’s lymphoma. Our current functional analyses provide the first in vitro evidence further demonstrating that cells with RNA interference-mediated depletion of NPAS2 fail to exhibit the expected cell cycle delay in response to mutagen treatment. DNA repair capacity, as measured by the comet assay, is also impaired. Moreover, a pathway-based PCR expression array of genes important for DNA damage signaling demonstrated that knockdown of NPAS2 significantly represses the expression of several cell cycle and DNA repair genes. Thus, NPAS2 may play a role in tumorigenesis by affecting expression of cancer-related genes, and could be considered a novel tumor suppressor.