分类： 生物学 >> 生物物理学 提交时间： 2016-05-11
摘要： Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG). In this study we used mouse embryonic stem (MES) and mouse embryonic fibroblast (MEF) cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9-deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs) in Rad9(-/-) MES and Mdc1(-/-) MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9(-/-) MES. As the exposure to SMG was prolonged, Rad9(-/-) MES cells adapted to the SMG disturbance by reducing the induced DNA lesions. The induced DNA lesions in Rad9(-/-) MES were due to SMG-induced reactive oxygen species (ROS). Interestingly, Mdc1(-/-) MEF cells were only partially adapted to the SMG disturbance. That is, the induced DNA lesions were reduced over time, but did not return to the control level while ROS returned to a control level. In addition, ROS was only partially responsible for the induced DNA lesions in Mdc1(-/-) MEF cells. Taken together, these data suggest that SMG is a weak genomic DNA stress and can aggravate genomic instability in cells with DNA damage response (DDR) defects.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-11
Zhang, Junjie
Zhu, Lining
Lu, Xiaolu
Wang, Yi
Gao, Shou-jiang
Feng, Pinghui
Feldman, Emily R.
Keyes, Lisa R.
Tibbetts, Scott A.
Fan, Hui
Feng, Hao
Xia, Zanxian
Xia, Zanxian
Sun, Jiya
Jiang, Taijiao
Sun, Jiya
Jiang, Taijiao
Sun, Jiya
Jiang, Taijiao
Jiang, Taijiao
摘要： Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumors, particularly in in immune-compromised individuals. Due to the stringent host tropism, rodents are resistant to infection by human gamma herpesviruses, creating a significant barrier for the in vivo study of viral genes that contribute to tumorigenesis. The closely-related murine gamma herpesvirus 68 (gamma HV68) efficiently infects laboratory mouse strains and establishes robust persistent infection without causing apparent disease. Here, we report that a recombinant gamma HV68 carrying the KSHV G protein-coupled receptor (kGPCR) in place of its murine counterpart induces angiogenic tumors in infected mice. Although viral GPCRs are conserved in all gamma herpesviruses, kGPCR potently activated downstream signaling and induced tumor formation in nude mouse, whereas gamma HV68 GPCR failed to do so. Recombinant gamma HV68 carrying kGPCR demonstrated more robust lytic replication ex vivo than wild-type gamma HV68, although both viruses underwent similar acute and latent infection in vivo. Infection of immunosuppressed mice with gamma HV68 carrying kGPCR, but not wild-type gamma HV68, induced tumors in mice that exhibited angiogenic and inflammatory features shared with human Kaposi's sarcoma. Immunohistochemistry staining identified abundant latently-infected cells and a small number of cells supporting lytic replication in tumor tissue. Thus, mouse infection with a recombinant gamma HV68 carrying kGPCR provides a useful small animal model for tumorigenesis induced by a human gamma herpesvirus gene in the setting of a natural course of infection.
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