Ethylene supports colonization of plant roots by the mutualistic fungus Piriformospora indica

The mutualistic basidiomycete Piriformospora indica colonizes roots of mono- and dicotyledonous plants, and thereby improves plant health and yield. Given the capability of P. indica to colonize a broad range of hosts, it must be anticipated that the fungus has evolved efficient strategies to overcome plant immunity and to establish a proper environment for nutrient acquisition and reproduction. Global gene expression studies in barley identified various ethylene synthesis and signaling components that were differentially regulated in P. indica-colonized roots. Based on these findings we examined the impact of ethylene in the symbiotic association. The data presented here suggest that P. indica induces ethylene synthesis in barley and Arabidopsis roots during colonization. Moreover, impaired ethylene signaling resulted in reduced root colonization, Arabidopsis mutants exhibiting constitutive ethylene signaling, -synthesis or ethylene-related defense were hyper-susceptible to P. indica. Our data suggest that ethylene signaling is required for symbiotic root colonization by P. indica

<span style="font-size: 15.5pt;mso-bidi-font-size:10.5pt;font-family:Fd5683-Identity-H;mso-bidi-font-family: Fd5683-Identity-H">Symbiosis between <i style="mso-bidi-font-style:normal"><span style="font-size:18.0pt;mso-bidi-font-size:13.0pt;font-family:Fd5690-Identity-H; mso-bidi-font-family:Fd5690-Identity-H">Frankia</span></i><span style="font-size:18.0pt;mso-bidi-font-size:13.0pt;font-family:Fd5690-Identity-H; mso-bidi-font-family:Fd5690-Identity-H"> <span style="font-size:15.5pt; mso-bidi-font-size:10.5pt;font-family:Fd5683-Identity-H;mso-bidi-font-family: Fd5683-Identity-H">and actinorhizal plants: Root nodules of non-legumes </span></span></span>

1165-1183<span style="font-size: 12.5pt;mso-bidi-font-size:7.5pt;font-family:Fd487971-Identity-H;mso-bidi-font-family: Fd487971-Identity-H">In actinorhizal symbioses, filamentous nitrogen-fixing soil bacteria of the genus <span style="font-size:13.0pt;mso-bidi-font-size:8.0pt;font-family:Fd429390-Identity-H; mso-bidi-font-family:Fd429390-Identity-H">Frankia<span style="font-size:13.0pt;mso-bidi-font-size:8.0pt;font-family:Fd429390-Identity-H; mso-bidi-font-family:Fd429390-Identity-H"> <span style="font-size:12.5pt; mso-bidi-font-size:7.5pt;font-family:Fd487971-Identity-H;mso-bidi-font-family: Fd487971-Identity-H">induce the formation of nodules on the roots of a diverse group of dicotyledonous plants representing trees or woody shrubs, with one exception, <i style="mso-bidi-font-style: normal"><span style="font-size:13.0pt;mso-bidi-font-size:8.0pt;font-family: Fd429390-Identity-H;mso-bidi-font-family:Fd429390-Identity-H">Datisca<span style="font-size:13.0pt;mso-bidi-font-size:8.0pt;font-family:Fd429390-Identity-H; mso-bidi-font-family:Fd429390-Identity-H"> glomerata. <span style="font-size:12.5pt;mso-bidi-font-size:7.5pt;font-family:Fd487971-Identity-H; mso-bidi-font-family:Fd487971-Identity-H">In the nodules, <span style="font-size:13.0pt;mso-bidi-font-size: 8.0pt;font-family:Fd429390-Identity-H;mso-bidi-font-family:Fd429390-Identity-H">Frankia<span style="font-size:13.0pt;mso-bidi-font-size:8.0pt;font-family:Fd429390-Identity-H; mso-bidi-font-family:Fd429390-Identity-H"> <span style="font-size:12.5pt; mso-bidi-font-size:7.5pt;font-family:Fd487971-Identity-H;mso-bidi-font-family: Fd487971-Identity-H">fixes nitrogen and exports the products to the plant cytoplasm, while being supplied with carbon sources by the host. Possibly due to the diversity of the host plants, actinorhizal nodules show considerable variability with regard to structure, oxygen protection mechanisms and physiology. Actinorhizal and legume-rhizobia symbioses are evolutionary related and share several features. </span

Truncated hemoglobins in actinorhizal nodules of Datisca glomerata

Three types of hemoglobins exist in higher plants, symbiotic, non-symbiotic, and truncated hemoglobins. Symbiotic (class II) hemoglobins play a role in oxygen supply to intracellular nitrogen-fixing symbionts in legume root nodules, and in one case ( Parasponia Sp.), a non-symbiotic (class I) hemoglobin has been recruited for this function. Here we report the induction of a host gene, dgtrHB1, encoding a truncated hemoglobin in Frankia-induced nodules of the actinorhizal plant Datisca glomerata. Induction takes place specifically in cells infected by the microsymbiont, prior to the onset of bacterial nitrogen fixation. A bacterial gene (Frankia trHBO) encoding a truncated hemoglobin with O (2)-binding kinetics suitable for the facilitation of O (2) diffusion ( ) is also expressed in symbiosis. Nodule oximetry confirms the presence of a molecule that binds oxygen reversibly in D. glomerata nodules, but indicates a low overall hemoglobin concentration suggesting a local function. Frankia trHbO is likely to be responsible for this activity. The function of the D. glomerata truncated hemoglobin is unknown; a possible role in nitric oxide detoxification is suggested

Pharmacologic Inhibitor of DNA-PK, M3814, Potentiates Radiotherapy and Regresses Human Tumors in Mouse Models.

Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials

Protein conformational flexibility modulates kinetics and thermodynamics of drug binding

An understanding of the dynamics of drug binding and unbinding processes is important for drug discovery. Here, the authors give insights into the binding mechanism of small drug-like molecules to human Hsp90 by combining thermodynamics and kinetics studies as well as molecular dynamics simulations