MRG15 is a conserved chromodomain protein that associates with histone deacetylases (HDACs

SummaryPALB2 physically and functionally connects the proteins encoded by the BRCA1 and BRCA2 breast and ovarian cancer genes into a DNA-damage-response network. However, it remains unclear how these proteins associate with chromatin that contains damaged DNA. We show here that PALB2 binds directly to a conserved chromodomain protein, MRG15, which is a component of histone acetyltransferase-deacetylase complexes. This interaction was identified by analysis of purified MRG15-and PALB2-containing protein complexes. Furthermore, MRG15 interacts with the entire BRCA complex, which contains BRCA1, PALB2, BRCA2 and RAD51. Interestingly, MRG15-deficient cells, similarly to cells deficient in PALB2 or BRCA2, showed reduced efficiency for homology-directed DNA repair and hypersensitivity to DNA interstrand crosslinking agents. Additionally, knockdown of MRG15 diminished the recruitment of PALB2, BRCA2 and RAD51 to sites of DNA damage and reduced chromatin loading of PALB2 and BRCA2. These results suggest that MRG15 mediates DNA-damage-response functions of the BRCA complex in chromatin.

Background: Dynamic changes in histone modifications and chromatin structure are tightly linked to transcriptional regulation. Results: KDM5A, a histone H3K4 demethylase, physically interacts with the nucleosome remodeling and deacetylase (NuRD) complex. Conclusion: KDM5A and the NuRD complex cooperatively function to control developmentally regulated genes. Significance: Elucidating the functional interplay between histone-modifying enzymes and chromatin remodeling machineries helps clarify development-related gene regulation.

Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cellcycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phasedependent fluorescent marker Fucci to distinguish cells in G 1 -phase and those in S þ G 2 /M phases. Fucci-labeled cells served as splenic xenograft transplants in super-immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G 1 -phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G 2 -M phases, suggesting accelerated glycolysis in G 1 -phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G 2 -M, and G 1 phases suggested that efflux of lactate was elevated significantly in G 1 -phase. By contrast, ATP production in G 2 -M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G 1 and G 2 -M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild-type cells. Thus, as the cell cycle progressed from G 2 -M to G 1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased.Implications: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. Mol Cancer Res; 11(9); 973-85. Ó2013 AACR.

The energy metabolism of the failing heart is characterized by reduced fatty acid (FA) oxidation and an increase in glucose utilization. However, little is known about how energy metabolism-function relationship is relevant to pathophysiology of heart failure. Recent study showed that the genetic deletion of CD36 (CD36KO), which causes reduction in FA use with an increased reliance on glucose, accelerates the progression from compensated hypertrophy to heart failure. Here, we show the mechanisms by which CD36 deletion accelerates heart failure in response to pressure overload. CD36KO mice exhibited contractile dysfunction and death from heart failure with enhanced cardiac hypertrophy and interstitial fibrosis when they were subjected to transverse aortic constriction (TAC). The pool size in the TCA cycle and levels of high-energy phosphate were significantly reduced in CD36KO-TAC hearts despite an increase in glycolytic flux. De novo synthesis of non-essential amino acids was facilitated in CD36KO-TAC hearts, which could cause a further decline of the pool size. The ingestion of a diet enriched in medium-chain FA improved cardiac dysfunction in CD36KO-TAC hearts. These findings suggest that myocardial FA uptake through CD36 is indispensable for sufficient ATP production and for preventing an increased glycolytic flux-mediated structural remodeling during pressure overload-induced hypertrophy.