Chromosomal Proteins, Non-Histone ; chemistry ; genetics ; metabolism ; HeLa Cells ; Histones ; chemistry ; genetics ; metabolism ; Humans ; Protein Domains

Animals ; Chromosomal Proteins, Non-Histone ; chemistry ; genetics ; metabolism ; Humans ; Models, Molecular ; Mutation ; Transcription Factors ; chemistry ; genetics ; metabolism

Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatin-binding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.
Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism/*physiology ; DNA Damage/genetics/*physiology ; DNA Repair/genetics/*physiology ; Humans ; Mice ; Models, Biological ; Neoplasms/*genetics ; Nerve Tissue Proteins/genetics/metabolism/*physiology

Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatin-binding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.
Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism/*physiology ; DNA Damage/genetics/*physiology ; DNA Repair/genetics/*physiology ; Humans ; Mice ; Models, Biological ; Neoplasms/*genetics ; Nerve Tissue Proteins/genetics/metabolism/*physiology

OBJECTIVETo explore the role of centromere protein H (CENP-H) in the proliferation of human gastric cancer cells.

METHODSRT-PCR and Western blot analysis were employed to examine the mRNA and protein expressions of CENP-H in 7 human gastric cancer cell lines and immortalized human gastric epithelial cells (GES-1). The cells were infected with the retrovirus vectors pMSCV-CENP-H or CENP-H-RNAi to establish stable cell lines with high CENP-H expression or CENP-H expression interference. MTT assay and colony formation assay were used to examine the changes in the cell proliferation after the infection.

RESULTSCENP-H was over-expressed in gastric cancer cell lines AGS, BGC823, SGC-7901, MKN45, HGC27, MGC-803 and MKN28 at both mRNA and protein levels. The established AGS/CENP-H cell line with increased CENP-H expression showed enhanced proliferative activity, while the cell line MGC-803/CENP-H-RNAi with CENP-H expression interference showed an obviously lowered proliferation ability.

CONCLUSIONCENP-H promotes the proliferation of human gastric cancer cells, suggesting its important role in the occurrence and development of gastric cancer.

Cell Line, Tumor ; Cell Proliferation ; Chromosomal Proteins, Non-Histone ; genetics ; metabolism ; Humans ; RNA, Messenger ; genetics ; metabolism ; Real-Time Polymerase Chain Reaction ; Stomach Neoplasms ; metabolism ; pathology

Animals ; Autoantigens ; genetics ; metabolism ; physiology ; Centromere Protein A ; Chromosomal Instability ; Chromosomal Proteins, Non-Histone ; genetics ; metabolism ; physiology ; Gene Expression Regulation, Neoplastic ; Humans ; Kinetochores ; metabolism ; Mitosis ; physiology ; Rectal Neoplasms ; genetics ; metabolism ; pathology ; Spindle Apparatus ; metabolism

This study was purposed to investigate the relationship between brd7 gene and differentiation of leukemia cells and the role of brd7 gene in differentiation of leukemia cells. The HL-60 and K562 cell lines were induced by all-trans retinoic acid (ATRA) for 7 days, then the cell morphologic change was observed under inverted microscope with Wright-Giema staining, the expression level of CD11b was detected by flow cytometry for evaluating cell differentiation level, the expression changes of BRD7 protein before inducing differentiation and in process of cell differentiation were determined by Western blot. The results showed that ATRA could inhibit the proliferation and induce differentiation of HL-60 cells, but no differentiation in K562 cells was induced by ATRA. The level of CD11b expression in HL-60 cells was up-regulated gradually during ATRA-induced cell differentiation. The expression of BRD7 protein increased markedly along with differentiation of HL-60 cells towards granulocytes. However, BRD7 protein did not significantly alter in K562 cells in which inducing differentiation was not found. It is concluded that brd7 gene expression enhances as the HL-60 cells differentiate, underlying which the mechanism remains to clarify.
CD11b Antigen ; metabolism ; Cell Differentiation ; drug effects ; Chromosomal Proteins, Non-Histone ; genetics ; metabolism ; Gene Expression Regulation, Leukemic ; drug effects ; HL-60 Cells ; Humans ; K562 Cells ; Tretinoin ; pharmacology

Genetic information stored in DNA is accurately copied and transferred to subsequent generations through DNA replication. This process is accomplished through the concerted actions of highly conserved DNA replication components. Epigenetic information stored in the form of histone modifications and DNA methylation, constitutes a second layer of regulatory information important for many cellular processes, such as gene expression regulation, chromatin organization, and genome stability. During DNA replication, epigenetic information must also be faithfully transmitted to subsequent generations. How this monumental task is achieved remains poorly understood. In this review, we will discuss recent advances on the role of DNA replication components in the inheritance of epigenetic marks, with a particular focus on epigenetic regulation in fission yeast. Based on these findings, we propose that specific DNA replication components function as key regulators in the replication of epigenetic information across the genome.
Cdc20 Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Centromere ; metabolism ; Chromatin ; metabolism ; Chromosomal Proteins, Non-Histone ; metabolism ; DNA Replication ; DNA, Fungal ; metabolism ; Epigenesis, Genetic ; Histones ; metabolism ; Schizosaccharomyces ; genetics ; metabolism ; Schizosaccharomyces pombe Proteins ; antagonists & inhibitors ; genetics ; metabolism

OBJECTIVE: To localize and define the region of nucleus export signal (NES) on BRD7, and determine the role of this region in nucleus export of the external protein. METHODS: Based on an in vitro expressed model of green fluorescence protein (GFP), we performed DNA walking analysis to set BRD7 into several sections according to the structural characteristics of BRD7, investigated the effect of different sections of BRD7 on nucleus export of GFP, defined the region of nucleus export signal sequence of BRD7, and further ascertained the content of amino acids in BRD7 and potential localization of BRD7 NES by bioinformatics. RESULTS: B7C1 fragments ranged from aa219 to aa450 in BRD7 were found to target the external protein GFP into the cytoplasm detected by GFP direct fluorescence, which could be inhibited by NES inhibitor Leptomycin B (LMB). This region was rich in hydrophobic amino acid residues but no typical NES with characteristics of leucine-rich sequence by bioinformatics. CONCLUSION The region from aa219 to aa450 is primarily defined as an atypical NES in BRD7.
Animals ; Base Sequence ; COS Cells ; Cell Nucleus ; metabolism ; Chlorocebus aethiops ; Chromosomal Proteins, Non-Histone ; genetics ; metabolism ; Cytoplasm ; metabolism ; Escherichia coli ; genetics ; metabolism ; Green Fluorescent Proteins ; genetics ; Humans ; Molecular Sequence Data ; Nuclear Export Signals ; Recombinant Proteins ; genetics ; metabolism

There is obvious allele disequilibrium in nasopharyngeal carcinoma at chromosome 3p, 9p, 6q, 11q, 13q and 14q. Nasopharyngeal carcinoma (NPC) susceptibility/suppressor gene candidates were obtained by molecular biology methods,such as cDNA representational difference ana-lysis. The functional research of NPC susceptibility/ suppressor gene candidates indicated: (1) The increased expression of Cx contributed to obstacles of gap junctional intercellular communication (GJIC), and resulted an aberration of GJIC; (2) BRD7, a transcript factor, was associated with cell cycle regulation; (3) NAG7,an estrogen receptor repressor, inhibited the invasive potential of human NPC cells by regulating ERalpha expression and the H-ras/p-c-Raf and JNK/AP-1/MMP1 signaling pathways; (4) NGX6, a metastasis-associated protein, can negative-regulate EGF/Ras/MAPK signaling transduction pathway, and interact with ezrin protein to inhibit invasion and metastasis of NPC cells; (5) SPLUNC1, a secreted protein, can inhibit the bacterium clone formation, and is an innate immune molecule. These data will lay an important foundation for the NPC mechanism.
Biomarkers, Tumor ; Cell Cycle Proteins ; genetics ; Chromosomal Proteins, Non-Histone ; genetics ; Genomics ; methods ; Glycoproteins ; genetics ; Humans ; Membrane Proteins ; genetics ; Nasopharyngeal Neoplasms ; genetics ; metabolism ; pathology ; Phosphoproteins ; genetics ; RNA, Long Noncoding ; RNA, Untranslated ; Tumor Cells, Cultured ; Tumor Suppressor Proteins ; genetics