The PHD3 Domain of MLL Acts as a CYP33-Regulated Switch between MLL-Mediated Activation and Repression,

The <i>mixed lineage leukemia</i> (<i>MLL</i>) gene plays a critical role in epigenetic regulation of gene expression and is a frequent target of chromosomal translocations leading to leukemia. MLL plant homeodomain 3 (PHD3) is lost in all <i>MLL</i> translocation products, and reinsertion of PHD3 into MLL fusion proteins abrogates their transforming activity. PHD3 has been shown to interact with the RNA-recognition motif (RRM) domain of human nuclear Cyclophilin33 (CYP33). Here, we show that CYP33 mediates downregulation of the expression of MLL target genes <i>HOXC8</i>, <i>HOXA9</i>, <i>CDKN1B</i>, and <i>C</i>-<i>MYC</i>, in a proline isomerase-dependent manner. This downregulation correlates with the reduction of trimethylated lysine 4 of histone H3 (H3K4me3) and histone H3 acetylation. We have structurally characterized both the PHD3 and CYP33 RRM domains and analyzed their binding to one another. The PHD3 domain binds H3K4me3 (preferentially) and the CYP33 RRM domain at distinct sites. Our binding data show that binding of H3K4me3 to PHD3 and binding of the CYP33 RRM domain to PHD3 are mutually inhibitory, implying that PHD3 is a molecular switch for the transition between activation and repression of target genes. To explore the possible mechanism of CYP33/PHD3-mediated repression, we have analyzed the CYP33 proline isomerase activity on various H3 and H4 peptides and shown selectivity for two sites in H3. Our results provide a possible mechanism for the MLL PHD3 domain to act as a switch between activation and repression

Isoprene NO₃ Oxidation Products from the RO₂ + HO₂ Pathway

We describe the products of the reaction of the hydroperoxy radical (HO₂) with the alkylperoxy radical formed following addition of the nitrate radical (NO₃) and O₂ to isoprene. NO₃ adds preferentially to the C₁ position of isoprene (>6 times more favorably than addition to C₄), followed by the addition of O₂ to produce a suite of nitrooxy alkylperoxy radicals (RO₂). At an RO₂ lifetime of ∼30 s, δ-nitrooxy and β-nitrooxy alkylperoxy radicals are present in similar amounts. Gas-phase product yields from the RO₂ + HO₂ pathway are identified as 0.75–0.78 isoprene nitrooxy hydroperoxide (INP), 0.22 methyl vinyl ketone (MVK) + formaldehyde (CH₂O) + hydroxyl radical (OH) + nitrogen dioxide (NO₂), and 0–0.03 methacrolein (MACR) + CH₂O + OH + NO₂. We further examined the photochemistry of INP and identified propanone nitrate (PROPNN) and isoprene nitrooxy hydroxyepoxide (INHE) as the main products. INHE undergoes similar heterogeneous chemistry as isoprene dihydroxy epoxide (IEPOX), likely contributing to atmospheric secondary organic aerosol formation

Gas-Phase Reactions of Isoprene and Its Major Oxidation Products

Isoprene carries approximately half of the flux of non-methane volatile organic carbon emitted to the atmosphere by the biosphere. Accurate representation of its oxidation rate and products is essential for quantifying its influence on the abundance of the hydroxyl radical (OH), nitrogen oxide free radicals (NO_<i>x</i>), ozone (O₃), and, via the formation of highly oxygenated compounds, aerosol. We present a review of recent laboratory and theoretical studies of the oxidation pathways of isoprene initiated by addition of OH, O₃, the nitrate radical (NO₃), and the chlorine atom. From this review, a recommendation for a nearly complete gas-phase oxidation mechanism of isoprene and its major products is developed. The mechanism is compiled with the aims of providing an accurate representation of the flow of carbon while allowing quantification of the impact of isoprene emissions on HO_<i>x</i> and NO_<i>x</i> free radical concentrations and of the yields of products known to be involved in condensed-phase processes. Finally, a simplified (reduced) mechanism is developed for use in chemical transport models that retains the essential chemistry required to accurately simulate isoprene oxidation under conditions where it occurs in the atmosphereabove forested regions remote from large NO_<i>x</i> emissions