Functional importance and divergence of plant apurinic/apyrimidinic endonucleases in somatic and meiotic DNA repair.

Apurinic/apyrimidinic (AP) sites are one of the most abundant DNA lesions and are mainly repaired by AP endonucleases (APEs). While most eukaryotic genomes encode two APEs, plants usually possess three APEs, namely APE1L, APE2, and ARP. To date, the biological relevance and functional divergence of plant APEs are unclear. Here, we show that the three plant APEs have ancient origins, with the APE1L clade being plant-specific. In Arabidopsis thaliana, simultaneously mutating APE1L and APE2, but not ARP alone or in combination with either APE1L or APE2, results in clear developmental defects linked to genotoxic stress. Genetic analyses indicated that the three plant APEs have different substrate preferences in vivo. ARP is mainly responsible for AP site repair, while APE1L and APE2 prefer to repair 3'-blocked single-stranded DNA breaks. We further determined that APEs play an important role in DNA repair and the maintenance of genomic integrity in meiotic cells. The ape1l ape2 double mutant exhibited a greatly enhanced frequency of sporulation 1 (SPO11-1)-dependent and SPO11-1-independent double-stranded DNA breaks. The DNA damage response (DDR) was activated in ape1l ape2 to trigger pollen abortion. Our findings suggest functional divergence of plant APEs and reveal important roles of plant APEs during vegetative and reproductive development.

The Arabidopsis ATR-SOG1 signaling module regulates pleiotropic developmental adjustments in response to 3'-blocked DNA repair intermediates.

Base excision repair and active DNA demethylation produce repair intermediates with DNA molecules blocked at the 3'-OH end by an aldehyde or phosphate group. However, both the physiological consequences of these accumulated single-strand DNAs break with 3'-blocked ends (DNA 3'-blocks) and the signaling pathways responding to unrepaired DNA 3'-blocks remain unclear in plants. Here, we investigated the effects of DNA 3'-blocks on plant development using the zinc finger DNA 3'-phosphoesterase (zdp) AP endonuclease2 (ape2) double mutant, in which 3'-blocking residues are poorly repaired. The accumulation of DNA 3'-blocked triggered diverse developmental defects that were dependent on the ATM and RAD3-related (ATR)-suppressor of gamma response 1 (SOG1) signaling module. SOG1 mutation rescued the developmental defects of zdp ape2 leaves by preventing cell endoreplication and promoting cell proliferation. However, SOG1 mutation caused intensive meristematic cell death in the radicle of zdp ape2 following germination, resulting in rapid termination of radicle growth. Notably, mutating FORMAMIDOPYRIMIDINE DNA GLYCOSYLASE (FPG) in zdp ape2 sog1 partially recovered its radicle growth, demonstrating that DNA 3'-blocks generated by FPG caused the meristematic defects. Surprisingly, despite lacking a functional radicle, zdp ape2 sog1 mutants compensated the lack of root growth by generating anchor roots having low levels of DNA damage response. Our results reveal dual roles of SOG1 in regulating root establishment when seeds germinate with excess DNA 3'-blocks.

New Promises from an Old Friend: Iodine-Rich Compounds as Prospective Energetic Biocidal Agents.

For a very long time, frequent occurrences of biocrises have wreaked havoc on human beings, animals, and the environment. As a result, it is necessary to develop biocidal agents to destroy or neutralize active agents by releasing large amounts of strong biocides which are obtained upon detonation. Iodine is an efficient biocidal agent for bacteria, fungi, yeasts, viruses, spores, and protozoan parasites, and it is the sole element in the periodic table that can destroy microbes without contaminating the environment. Based on chemical biology, the mechanism of iodine as a bactericide may arise from oxidation and iodination reactions of cellular proteins and nucleic acids. However, because of the high vapor pressure causing elemental iodine to sublime readily at room temperature, it is inconvenient to use this material in its normal solid state directly as a biocidal agent under ambient conditions. Iodine-rich compounds where iodine is firmly bonded in molecules as a C-I or I-O moiety have been observed to be among the most promising energetic biocidal compounds. Gaseous products comprised of large amounts of iodine or iodine-containing components as strong biocides are released in the decomposition or explosion of iodine-rich compounds. Because of the detonation pressure, the iodine species are distributed over a large area greatly improving the efficacy of the system and requiring considerably less effort compared to traditional biocidal methods. The commercially available tetraiodomethane and tetraiodoethene, which possess superb iodine content also have the disadvantages of volatility, light sensitivity, and chemically reactivity, and therefore, are not suitable for use directly as biocidal agents. It is absolutely critical to synthesize new iodine-rich compounds with good thermal and chemical stabilities.In this Account, we describe our strategies for the syntheses of energetic iodine-rich compounds while maintaining the maximum iodine content with concomitant stability and routes for the synthesis of oxygen-containing iodine-rich compounds to improve the oxygen balance and achieve both high-energy and high-iodine content. In the other work, which involves cocrystals, iodine-containing polymers were also summarized. It is hoped that this Account will provide guidelines for the design and syntheses of new iodine-rich compounds and a route for the development of inexpensive, more efficient, and safer iodine-rich antibiological warfare agents of the future.

N-Functionalization of 5-Aminotetrazoles: Balancing Energetic Performance and Molecular Stability by Introducing ADNP.

5-aminotetrazole is one of the most marked high-nitrogen tetrazole compounds. However, the structural modification of 5-aminotetrazole with nitro groups often leads to dramatically decreased molecular stability, while the N-bridging functionalization does not efficiently improve the density and performance. In this paper, we report on a straightforward approach for improving the density of 5-aminotetrazole by introducing 4-amino-3,5-dinitropyrazole. The following experimental and calculated properties show that nitropyrazole functionalization competes well with energetic performance and mechanic sensitivity. All compounds were thoroughly characterized using IR and NMR spectroscopy, elemental analysis, and differential scanning calorimetry (DSC). Two energetic compounds (DMPT-1 and DMPT-2) were further confirmed by implementing single-crystal X-ray diffraction studies. Compound DMPT-1 featured a high crystal density of 1.806 g cm-3, excellent detonation velocity (vD = 8610 m s-1), detonation pressure (P = 30.2 GPa), and impact sensitivity of 30 J.

A Dual-Targeted Organic Photothermal Agent for Enhanced Photothermal Therapy.

The development of highly effective anticancer drugs that cause minimal damage to the surrounding normal tissues is a challenging topic in cancer therapy. Herein, we demonstrate a dual-targeted organic molecule that functions as a photothermal agent by actively targeting tumor tissue and mitochondria to selectively kill cancer cells. The synthesized photothermal agent exhibited high photothermal conversion efficiency, low cytotoxicity, and good biological compatibility. In vivo experiments showed an excellent tumor inhibitory effect of the dual-targeted photothermal agent.

Simultaneous Fluorescence Visualization of Epithelial-Mesenchymal Transition and Apoptosis Processes in Tumor Cells for Evaluating the Impact of Epithelial-Mesenchymal Transition on Drug Efficacy.

The epithelial-mesenchymal transition (EMT) process plays a pivotal role in acquiring invasive and metastatic properties and has been recognized as a crucial driver of epithelial-derived tumor malignancies. It is necessary to determine the role of EMT in promoting or suppressing carcinoma progression through investigating the relationship between EMT and apoptosis. We designed a multicolor fluorescent nanoprobe for simultaneously imaging the epithelial biomarker E-cadherin mRNA, the mesenchymal marker vimentin mRNA, and the apoptotic marker caspase-3. EMT and apoptosis progresses could be visually detected, which were used to study the effect of EMT on apoptosis and further assess the influence of EMT on drug efficacy in different cancer cells. We believe the designed nanoprobe can offer a new strategy for visualizing EMT and apoptosis in tumor cells and will be a promising tool to investigate the efficiency of drugs targeting EMT-related therapies in living cells.

Polyiodo Azole-Based Metal-Organic Framework Energetic Biocidal Material for Synergetic Sterilization Applications.

Biological hazards caused by bacteria, viruses, and toxins have become a major survival and development issue facing the international community. However, the traditional method of disinfection and sterilization is helpless in dealing with viruses that spread quickly and are highly infectious. Metal-organic framework (MOF) biocidal materials hold promise as superior alternatives to traditional sterilization materials because of their stable framework structures and unique properties. Now, we demonstrate for the first time the synthesis of a MOF (TIBT-Cu) containing Cu metal centers and tetraiodo-4,4'-bi-1,2,4-triazole as the main ligand. This novel MOF biocidal material has good thermal stability (Td = 278 °C), excellent mechanical sensitivity, and a high bacteriostatic efficiency (>99.90%). Additionally, the particles produced by the combustion of TIBT-Cu are composed of active iodine substances and CuO particles, which can act synergistically against harmful microorganisms such as bacteria and viruses. This study provides a new perspective for the preparation of highly effective bactericidal materials.

An active tumor-targeting organic photochemotherapy agent with naproxen for enhanced cancer therapy.

An active tumor-targeting organic photochemotherapy agent via the combination of a an organic photothermal material and a naproxen prodrug was developed to precisely kill cancer cells and suppress the inflammatory response induced by cell necrosis; in vitro, and in vivo experiments illustrated its low cytotoxicity and excellent tumor inhibitory effect.

A self-assembly of an active tumor-targeted photothermal agent for enhanced anti-inflammatory cancer therapy.

A self-assembly of an active tumor-cell-targeted photothermal agent, functionalized with a cyclic Arg-Gly-Asp peptide and ibuprofen, for killing cancer cells and eliciting anti-inflammatory responses was developed. In vitro and in vivo experiments also demonstrated that the photothermal material exhibited low cytotoxicity, good biological compatibility and excellent tumor inhibitory effects.