FEBS Letters最新文献

CLOCK, BMAL1, and HIFs are basic helix-loop-helix and Per-Arnt-Sim domain (bHLH-PAS) proteins, which function as transcription factors. bHLH-PAS proteins are designated in two classes. Many class I proteins are regulated by environmental signals via their PAS domains, but such signals have not been identified for all. Class II (ARNTs and BMALs) are partners for Class I and can be regulated by synthetic PAS ligands. Previous studies suggested restricted dimerization for bHLH-PAS proteins. BMAL1 and BMAL2 were believed to dimerize only with CLOCK and NPAS2, while ARNT was thought to dimerize with most Class I proteins except for CLOCK and NPAS2. The logic underlying these assumptions was flawed, and evidence supports dimerization of both HIF1α and HIF2α with BMAL1.

The long lifespan of humans is often not matched with health span. Thus, there is a need for rejuvenation strategies. Here, we first discuss the evolutionary benefits of the long human lifespan, particularly when coupled with an extended health span. We then highlight the importance of understanding the complexity of aging before interfering with it. This raises the question of the optimal target for rejuvenation. We propose the blood system and hematopoietic stem cells (HSCs). Their decline is associated with dysfunction and disease in other organs, crystallizing them as a central player in organismal aging. We present rejuvenation strategies targeting the hematopoietic system, especially HSCs, and explore their systemic benefits. Overall, we summarize the potential of the blood system to reverse aging. Impact statement There is a current need to reduce the economic burden caused by aging-related diseases. In this perspective article, we discuss the evidence that supports that rejuvenating or delaying aging of the blood system has a beneficial and systemic impact on human health.

Intrinsically disordered protein regions (IDRs) are found across all domains of life and are characterized by a lack of stable 3D structure. Nevertheless, IDRs play critical roles in the most tightly regulated cellular processes, including in the core circadian clock. The molecular oscillator at the heart of circadian regulation leverages IDRs as dynamic interaction modules-for activation and repression, alike-to support robust timekeeping and expand clock output and regulation. Here, we cover the biophysical mechanisms conferred by IDRs and their modulators. We survey the IDRs in clock proteins that are widely prevalent from fungi to mammals and discuss the importance of IDRs to the core clock and beyond.

Protein pyrophosphorylation is an emerging, unusual posttranslational modification. This signaling mechanism can be driven by inositol pyrophosphate messengers, which can convert a prephosphorylated protein to the corresponding pyrophosphoprotein. Endogenous protein pyrophosphorylation influences various cellular processes and signaling pathways, including the regulation of rRNA synthesis and the modulation of vesicular trafficking. Herein, we will summarize the current detection and analysis methods that have established the occurrence of pyrophosphorylation. These methods have also been used to explore the effects of pyrophosphorylation on protein structure and function. Putative mechanisms for the regulation of this intriguing, understudied modification will be discussed. Finally, the future needs for this developing area of signal transduction research are highlighted.

Ribonucleotide reductases (RNRs) convert all four ribonucleotides to deoxyribonucleotides, providing essential building blocks for DNA biosynthesis and repair through radical-based catalysis. These functions are key to cellular proliferation and have made RNRs well established targets for antimicrobial and antiviral drugs and combination chemotherapies. Here, we describe a novel highly sensitive one-pot enzymatic assay, which amplifies RNR activity by coupling it to the synthesis of a fluorogenic RNA aptamer. We validated this approach by testing RNR activity under dNTP-limiting conditions to emulate RNR's complex allosteric regulatory patterns and by detecting the dose- and time-dependent inhibition of RNR by hydroxyurea. This unique assay builds on previous high-throughput screening assays for investigation of RNR's catalytic mechanisms by improving sensitivity and reducing readout timeframes. Impact statement Ribonucleotide reductases (RNRs) are essential for controlling cellular dNTP supply and are major targets in cancer, antiviral, and antimicrobial therapy. FLARE is a novel single-tube, real-time RNR assay, coupling dNTP synthesis to the transcription of a fluorogenic aptamer for continuous monitoring of activity, regulation, and inhibition using standard microplate readers.

Circadian transcription factors (TFs) orchestrate daily rhythms in gene expression to drive rhythmic biological functions. In mammals, this system relies on the TF CLOCK:BMAL1, which binds E-boxes to initiate rhythmic transcription. While traditionally viewed as a master activator, CLOCK:BMAL1 is now recognized to engage in additional regulatory functions that are essential for its activity. This perspective focuses on the mammalian circadian clock and integrates genomic, structural, and single-molecule footprinting data to highlight emerging insights into how CLOCK:BMAL1 regulates chromatin architecture, cooperates with other TFs, and coordinates complex enhancer dynamics. We propose an updated framework for how circadian TFs operate within dynamic and multifactorial chromatin landscapes, and prime cis-regulatory elements for rhythmic transcriptional bursts. We also discuss how this framework underlies circadian reprogramming and transcriptional plasticity.

Cells are constantly exposed to various sources of DNA damage, including radiation, chemicals, replicative stress and oxidative stress, that threaten genome stability. To ensure faithful DNA repair, transcription regulation needs to be tightly controlled. This regulation involves transcriptional suppression, selective activation of DNA repair-related genes and transcriptional recovery post-repair. Failure to properly modulate transcription during DNA damage can result in collisions between transcriptional and repair machineries, misregulation of repair genes and delayed recovery, ultimately compromising genomic integrity. Chromatin modifications play a central role in this process. These modifications include phosphorylation, methylation, acetylation and ubiquitination, which orchestrate DNA accessibility for repair machinery and fine-tune transcriptional responses. Absence of these modifications leads to inefficient DNA repair and transcriptional errors that are implicated in diseases such as cancer, premature ageing and neurodegenerative disorders. In this review, we delve into the role of various types of histone modifications, such as phosphorylation, methylation, acetylation and ubiquitination and how they regulate transcription in response to DNA damage. Impact Statement This review elucidates how histone modifications orchestrate transcription regulation during DNA damage response, safeguarding genome stability. We also discuss transcription dysregulation in diseases such as cancer and premature aging. Our review provide insights on chromatin-based repair pathways and guide researchers in developing therapeutic targets.

The LH2 complex is essential for light harvesting in many photosynthetic bacteria. To elucidate the specific structural role of carotenoids, we analyzed LH2 complexes from Ectothiorhodospira haloalkaliphila with inhibited carotenoid biosynthesis. This approach allowed us to study complexes incorporating the colorless carotenoid phytoene instead of the native, colored pigments. A 1.92 Å cryo-EM reconstruction revealed that phytoene fully substitutes for the native carotenoids while maintaining the octameric symmetry of the complex and the precise arrangement of bacteriochlorophylls. These results demonstrate that the architectural function of carotenoids in LH2 complexes is maintained even when their light-absorption capability is altered, providing new mechanistic insight into the structural basis of pigment–protein interactions in photosynthetic antenna complexes.

RETRACTION: F. Zhang, H. Ni, X. Li, H. Liu, T. Xi and L. Zheng, “ LncRNA FENDRR Attenuates Adriamycin Resistance via Suppressing MDR1 Expression Through Sponging HuR and miR-184 in Chronic Myelogenous Leukaemia Cells,” FEBS Letters 593, no. 15 (2019): 1993-2007, https://doi.org/10.1002/1873-3468.13480.

The above article, published online on 10 June 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, T. Xi and L. Zheng; the journal Editor-in-Chief, Michael Brunner; the Federation of European Biochemical Societies; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party. Several duplications were identified between Figures 1B, 2C, 2D, 2G, 3A, 3B, and 7D of this article and figures published in another article by two of the same authors. The authors contacted the journal and explained this was an inadvertent error that occurred during figure preparation as the studies were conducted simultaneously. However, due to the nature and extent of the duplications, the editors no longer have confidence in the results and conclusions reported in the paper. The co-authors, F. Zhang, H. Ni, X. Li and H. Liu did not respond to our notice of retraction.