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Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repairs prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7s deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

An efficient eight-step synthesis of the title compound, starting from oxoacetic acid monohydrate, was developed. Conden-sation of oxoacetic acid monohydrate with N,N-dimethylethana-mine followed by reductive amination and protection gave N-(tert-butoxycarbonyl)-N-[2-(dimethylamino)ethyl]glycine. Activation of this intermediate with 1,1'-carbonylbis-1H-imidazole followed by treatment with (methoxyamino)methane gave tert-butyl [2-(dimeth-ylamino)ethyl]{2-[methoxy(methyl)amino]-2-oxoethyl}carbamate, which upon reaction with [4-fluoro-3-(trifluoromethyl)phe-nyl]magnesium bromide, generated in situ, and subsequent deprot-ection gave 2-{[2-(dimethylamino)ethyl]amino}-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone dihydrochloride. Coupling of this diamine with an activated carboxylic acid gave tert-butyl 4-{1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate, which on treatment with sodium acetate in ethanol followed by deprotection in situ and neutralization gave the title compound in good yield. [ABSTRACT FROM AUTHOR]

A cone-nanolayer target that combines the advantages of the conical and layered geometries for electron acceleration in laser-target interaction is proposed. Two-dimensional particle-in-cell (PIC) simulations show that the cone-nanolayer target can enhance laser absorption and electron yield. With suitable choice of the laser and target parameters, the cone-nanolayer target can be a controllable source of hot electrons at desired energy ranges. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is a highly aggressive malignancy lacking clinically available targeted therapeutic agents. Super-enhancers (SEs) are crucial epigenetic cis-regulatory elements whose extensive reprogramming drives aberrant transcription in cancers. To study SE in GBC, the genomic distribution of H3K27ac is profiled in multiple GBC tissue and cell line samples to establish the SE landscape and its associated core regulatory circuitry (CRC). The biliary lineage factor SOX9 and Wnt pathway effector TCF7L2, two master transcription factor (TF) candidates identified by CRC analysis, are verified to co-occupy each other's SE region, forming a mutually autoregulatory loop to drive oncogenic SE reprogramming in a subset of GBC. The SOX9/TCF7L2 double-high GBC cells are highly dependent on the two TFs and enriched of SE-associated gene signatures related to stemness, ErbB and Wnt pathways. Patients with more such GBC cells exhibited significantly worse prognosis. Furthermore, SOX9/TCF7L2 double-high GBC preclinical models are found to be susceptible to SE-targeted CDK7 inhibition therapy in vitro and in vivo. Together, this study provides novel insights into the epigenetic mechanisms underlying the oncogenesis of a subset of GBCs with poorer prognosis and illustrates promising prognostic stratification and therapeutic strategies for treating those GBC patients in future clinical trials., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Transcription-coupled repair (TCR) is the major pathway to remove transcription-blocking lesions. Although discovered for nearly 40 years, the mechanism and critical players of mammalian TCR remain unclear. STK19 is a factor affecting cell survival and recovery of RNA synthesis in response to DNA damage, however, whether it is a necessary component for TCR is unknown. Here, we demonstrated that STK19 is essential for human TCR. Mechanistically, STK19 is recruited to damage sites through direct interaction with CSA. It can also interact with RNA polymerase II in vitro. Once recruited, STK19 plays an important role in UVSSA ubiquitination which is needed for TCR. STK19 also promotes TCR independent of UVSSA ubiquitination by stimulating TFIIH recruitment through its direct interaction with TFIIH. In summary, our results suggest that STK19 is a key factor of human TCR that links CSA, UVSSA ubiquitination and TFIIH loading, shedding light on the molecular mechanisms of TCR., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In this study, we propose two full-optical-setup and single-shot measurable approaches for complete characterization of attosecond pulses from surface high harmonic generation (SHHG): SHHG-SPIDER (spectral phase interferometry for direct electric field reconstruction) and SHHG-SEA-SPIDER (spatially encoded arrangement for SPIDER). 1D- and 2D-EPOCH PIC (particle-in-cell) simulations were performed to generate the attosecond pulses from relativistic plasmas under different conditions. Pulse trains dominated by single isolated peak as well as complex pulse train structures are extensively discussed for both methods, which showed excellent accuracy in the complete reconstruction of the attosecond field with respect to the direct Fourier transformed result. Kirchhoff integral theorem has been used for the near-to-far-field transformation. This far-field propagation method allows us to relate these results to potential experimental implementations of the scheme. The impact of comprehensive experimental parameters for both apparatus, such as spectral shear, spatial shear, cross-angle, time delay, and intensity ratio between the two replicas has been investigated thoroughly. These methods are applicable to complete characterization for SHHG attosecond pulses driven by a few to hundreds of terawatts femtosecond laser systems.

[equation: see text] An efficient one-pot route to unsymmetrical diorganyl selenides has been developed by ruthenium(III) chloride catalyzed reactions of dibenzyl or diphenyl diselenides with alkyl halides in the presence of zinc. Organic iodides, bromides, and activated chlorides underwent the reactions efficiently. Unreactive organic chlorides also underwent the same type of selenation with sodium bromide as the additive.