Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis.

Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here, we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes ("spermatoproteasomes") contain a spermatid/sperm-specific α subunit α4 s/PSMA8 and/or the catalytic ß subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.

Synergistic effects of combination treatment with bortezomib and doxorubicin in human neuroblastoma cell lines.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in infants. Currently, the mainstay of NB chemotherapy is combination treatment with some traditional drugs, but these combination regimens are always inefficient. METHODS: The aim of this study was to evaluate the inhibitory effect of a combination of doxorubicin and bortezomib, a novel anticancer drug and the first prote-asome inhibitor approved for the treatment of human malignant tumors, on the proliferation of two human NB cell lines, SK-N-SH and SH-SY5Y. The general mechanism underlying this combined effect was also investigated. Synergistic inhibitory effects on human NB cell proliferation were evaluated using the median-effect principle. The pro-apoptotic effects of these drugs were evaluated using double staining with annexin-V-FITC and propidium iodide. RESULTS: Synergistic inhibitory effects on proliferation were observed when a combination of bortezomib and doxorubicin was applied to cultured NB cells. A similar synergistic effect on apoptosis was also observed when the two drugs were used concurrently, which suggested that the possible mechanism underlying the observed synergistic inhibitory effect might be related to apoptosis. CONCLUSION: The combination of bortezomib and doxorubicin appears to be a promising strategy to treat NB.

[Screening genes of differential expression in BALB/C mice thymus: a pilot study of effect of salmon milt DNA (SMD) on age-related involutions].

OBJECTIVE: To investigate the effect and its mechanism of salmon milt DNA (SMD) on age-related involutions in mouse thymus. METHODS: Female BALB/C mice aged 10 months were divided randomly into three groups according to their weights. They were high dosage group (333.33 mg.kg(-1).b.w.d(-1)), low dosage group (166.67 mg.kg(-1).b.w.d(-1)) and control group (0 mg.kg(-1).b.w.d(-1)). After five weeks, their thymus indexes were measured and the thymocytes were counted and the thymus cortex thicknesses were also measured using Image-Pro Plus (version. 4.0) software in the thymus section. All the data were analyzed by SAS statistic software. Microarray technique was applied to screen the gene fragments, which were differentially expressed between the high dosage group and the control group, together with RT-PCR to further confirm some of them. RESULTS: No significant differences of the variables including body weight, thymus weight and thymus indexes among the three groups were found. The thymocytes quantities of thymus cortex and medulla in the high dosage group were significantly higher than those of the control group (P < 0.01 and P < 0.05, respectively). The thymus cortex thicknesses of both SMD supplement groups were significantly higher than that of the control group (P < 0.01 and P < 0.05 respectively). 112 differently expressed gene fragments were isolated. Furthermore, we found the fragments with the logged number of U23789, X80232 and Aw209102 were highly expressed in the high dosage group when RT-PCR technique was used. CONCLUSIONS: SMD may reverse the age-related involutions in mouse thymus via up-regulation the expression of proliferation related genes and via up-regulation the expression of development and differentiation related genes simultaneously.