DNA damage repair is crucial for the maintenance of genome integrity and cancer suppression. We found that loss of the mouse transcription factor YY1 resulted in polyploidy and chromatid aberrations, which are signatures of defects in homologous recombination. Further biochemical analyses identified a YY1 complex comprising components of the evolutionarily conserved INO80 chromatin-remodeling complex. Notably, RNA interference-mediated knockdown of YY1 and INO80 increased cellular sensitivity toward DNA-damaging agents. Functional assays revealed that both YY1 and INO80 are essential in homologous recombination-based DNA repair (HRR), which was further supported by the finding that YY1 preferentially bound a recombination-intermediate structure in vitro. Collectively, these observations reveal a link between YY1 and INO80 and roles for both in HRR, providing new insight into mechanisms that control the cellular response to genotoxic stress.Genomic instability is a hallmark of cancer development and progression. Defects in DNA double-strand break (DSB) repair are believed to be responsible for chromosomal rearrangements and can be rectified by homologous recombination, which is particularly active in the S and G2 phases of the cell cycle, or by nonhomologous end joining (NHEJ), active in G1 phase 1,2 . Homologous recombination is an important mechanism for the repair of damaged chromosomes and damaged replication forks, and for several other aspects of chromosome maintenance 3 . Furthermore, impairment of homologous recombination is probably one of the underlying causes of breast, ovarian and other cancers 4,5 . INO80, a member of the Snf2p family of DNA-dependent ATPases, has been shown to positively regulate homologous recombination in a number of organisms [6][7][8] . The Ino80 complex is evolutionarily conserved, and components of the complex have been identified in mammalian cells 9 induces phosphorylation of histone H2A, and the yeast INO80 complex is known to be recruited directly to DSBs through an interaction with the phosphorylated histone H2A 7,8,10,11 ; however, the precise function of INO80 in DSB repair and its recruitment to the damage site are not completely understood 12 .Yin Yang-1 (YY1) is a zinc finger-containing Polycomb group (PcG) transcription factor that is essential in development [13][14][15][16] . Recently, a number of studies have shown that loss of YY1 increases the p53 protein level 17,18 , raising the possibility that YY1 may contribute to the regulation of genomic integrity. To investigate this possibility, we used genetic, biochemical and proteomic approaches. We discovered essential roles for YY1 in the cellular response to genotoxic stress and in the maintenance of chromosomal stability. Furthermore, we found multiple lines of evidence that link YY1 and the ATP-dependent chromatin-remodeling complex INO80 in DNA repair. We identified a YY1 complex containing components of the INO80 complex and confirmed this interaction of YY1 with components of the INO80 complex by ad...

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Introduction Osteosarcoma is the most common primary malignancy of the bone among adolescents and children. Despite intensive chemotherapy and aggressive surgery, the 5-year survival rate of osteosarcoma still falls under 70%, mainly due to its tendency to metastasize and to develop drug resistance. Therefore, new treatments for osteosarcoma are urgently needed. HGF/c-Met signaling pathway, when dysregulated, is involved in the onset, progression and metastasis of various cancers, making the HGF/c-Met axis a promising therapeutic target. Methods In this study, we found Met to be a cancer-promoting gene in osteosarcoma as well, and aimed to investigate the role of a c-met inhibitor (PHA-665752) in osteosarcoma. For this purpose, two human osteosarcoma cell lines (143B and U2OS) were introduced in this study and treated with PHA-665752. CCK8 cell proliferation assay was performed to obtain the IC 50 value of PHA-665752 for 143B and U2OS. After that, colony formation assay, transwell migration and invasion assay and wound-healing assay were performed. Furthermore, a tumor-transplanted mouse model was used for in vivo experiments. Results Our results showed that PHA-665752 could suppress osteosarcoma progression, promote apoptosis and inhibit proliferation of human osteosarcoma cells. Moreover, we found ERK1/2 pathway to be an important mediator underlying the osteosarcoma-suppressing function of PHA-665752. LY3214996, a highly selective inhibitor of the ERK1/2 pathway, was able to antagonize the effects of PHA-665752 in osteosarcoma. Finally, in vivo experiments indicated that PHA-665752 suppressed tumor growth in a tumor-transplanted mouse model. Conclusion Taken together, Met provided a druggable target for osteosarcoma and PHA-665752 is a promising candidate for anti-osteosarcoma treatments.