Critical Reviews in Biochemistry and Molecular Biology最新文献

Found in virtually every organism, glycans are essential molecules that play important roles in almost every aspect of biology. The composition of glycome, the repertoire of glycans in an organism or a biological sample, is often found altered in many diseases, including cancer, infectious diseases, metabolic and developmental disorders. Understanding how glycosylation and glycomic changes enriches our knowledge of the mechanisms of disease progression and sheds light on the development of novel therapeutics. However, the inherent diversity of glycan structures imposes challenges on the experimental characterization of glycomes. Advances in high-throughput glycomic technologies enable glycomic analysis in a rapid and comprehensive manner. In this review, we discuss the analytical methods currently used in high-throughput glycomics, including mass spectrometry, liquid chromatography and lectin microarray. Concomitant with the technical advances is the integration of glycomics into systems biology in the recent years. Herein we elaborate on some representative works from this recent trend to underline the important role of glycomics in such integrated approaches to disease.

It is almost five decades since the discovery of the hypothalamic-pituitary-testicular axis. This refers to the hormonal axis that connects the hypothalamus, pituitary gland and testes, which in turn, regulates the production of spermatozoa through spermatogenesis in the seminiferous tubules, and testosterone through steroidogenesis by Leydig cells in the interstitium, of the testes. Emerging evidence has demonstrated the presence of a regulatory network across the seminiferous epithelium utilizing bioactive molecules produced locally at specific domains of the epithelium. Studies have shown that biologically active fragments are produced from structural laminin and collagen chains in the basement membrane. Additionally, bioactive peptides are also produced locally in non-basement membrane laminin chains at the Sertoli-spermatid interface known as apical ectoplasmic specialization (apical ES, a testis-specific actin-based anchoring junction type). These bioactive peptides are derived from structural laminins and/or collagens at the corresponding sites through proteolytic cleavage by matrix metalloproteinases (MMPs). They in turn serve as autocrine and/or paracrine factors to modulate and coordinate cellular events across the epithelium by linking the apical and basal compartments, the apical and basal ES, the blood-testis barrier (BTB), and the basement membrane of the tunica propria. The cellular events supported by these bioactive peptides/fragments include the release of spermatozoa at spermiation, remodeling of the immunological barrier to facilitate the transport of preleptotene spermatocytes across the BTB, and the transport of haploid spermatids across the epithelium to support spermiogenesis. In this review, we critically evaluate these findings. Our goal is to identify research areas that deserve attentions in future years. The proposed research also provides the much needed understanding on the biology of spermatogenesis supported by a local network of regulatory biomolecules.

Overproduction of reactive oxygen species and compromised antioxidant defenses perturb intracellular redox homeostasis and is associated with a myriad of human diseases as well as with the natural process of aging. Hydrogen sulfide (H₂S), which is biosynthesized by organisms ranging from bacteria to man, influences a broad range of physiological functions. A highly touted molecular mechanism by which H₂S exerts its cellular effects is via post-translational modification of the thiol redox proteome, converting cysteine thiols to persulfides, in a process referred to as protein persulfidation. The physiological relevance of this modification in the context of specific signal transmission pathways remains to be rigorously established, while a general protective role for protein persulfidation against hyper-oxidation of the cysteine proteome is better supported. A second mechanism by which H₂S modulates redox homeostasis is via remodeling the redox metabolome, targeting the electron transfer chain and perturbing the major redox nodes i.e. CoQ/CoQH₂, NAD⁺/NADH and FAD/FADH₂. The metabolic changes that result from H₂S-induced redox changes fan out from the mitochondrion to other compartments. In this review, we discuss recent developments in elucidating the roles of H₂S and its oxidation products on redox homeostasis and its role in protecting the thiol proteome.

Organisms from all domains of life invest a substantial amount of energy for the introduction of RNA modifications into nearly all transcripts studied to date. Instrumental analysis of RNA can focus on the modified residues and reveal the function of these epitranscriptomic marks. Here, we will review recent advances and breakthroughs achieved by NMR spectroscopy, sequencing, and mass spectrometry of the epitranscriptome.

Translation occurring on cytoplasmic mRNA is precisely governed at three consecutive stages, including initiation, elongation and termination. A growing body of evidence has revealed that an emerging epitranscriptomic code N⁶-methyladenosine (m⁶A), asymmetrically present in a large subset of coding and non-coding transcripts, is crucially required for mediating the translatomic stability. Through recruiting translation machinery proteins, serving as a physical barrier, or directing RNA structural rearrangement and mRNA looping formation, m⁶A has been decoded to modulate translational dynamics through potentially influencing the progress of different stages, thereby forming an additional layer of complexity to the regulation of translation. In this review, we summarize the current understanding of how m⁶A guides mRNA translation under normal and stress conditions, highlighting the divergent molecular mechanisms of multifarious regulation of m⁶A-mediated translation.

DNA damaging agents have been a cornerstone of cancer therapy for nearly a century. The discovery of many of these chemicals, particularly the alkylating agents, are deeply entwined with the development of poisonous materials originally intended for use in warfare. Over the last decades, their anti-proliferative effects have focused on the specific mechanisms by which they damage DNA, and the factors involved in the repair of such damage. Due to the variety of aberrant adducts created even for the simplest alkylating agents, numerous pathways of repair are engaged as a defense against this damage. More recent work has underscored the role of RNA damage in the cellular response to these agents, although the understanding of their role in relation to established DNA repair pathways is still in its infancy. In this review, we discuss the chemistry of alkylating agents, the numerous ways in which they damage nucleic acids, as well as the specific DNA and RNA repair pathways which are engaged to counter their effects.

SLX4 provides a molecular scaffold for the assembly of multiple protein complexes required for the maintenance of genome stability. It is involved in the repair of DNA crosslinks, the resolution of recombination intermediates, the response to replication stress and the maintenance of telomere length. To carry out these diverse functions, SLX4 interacts with three structure-selective endonucleases, MUS81-EME1, SLX1 and XPF-ERCC1, as well as the telomere binding proteins TRF2, RTEL1 and SLX4IP. Recently, SLX4 was shown to interact with MutSβ, a heterodimeric protein involved in DNA mismatch repair, trinucleotide repeat instability, crosslink repair and recombination. Importantly, MutSβ promotes the pathogenic expansion of CAG/CTG trinucleotide repeats, which is causative of myotonic dystrophy and Huntington's disease. The colocalization and specific interaction of MutSβ with SLX4, together with their apparently overlapping functions, are suggestive of a common role in reactions that promote DNA maintenance and genome stability. This review will focus on the role of SLX4 in DNA repair, the interplay between MutSβ and SLX4, and detail how they cooperate to promote recombinational repair and DNA crosslink repair. Furthermore, we speculate that MutSβ and SLX4 may provide an alternative cellular mechanism that modulates trinucleotide instability.

The known polyspecificity of antibodies, which is crucial for efficient immune response, is determined by the conformational flexibility and intrinsic disorder encoded in local peculiarities of the amino acid sequence of antibodies within or in the vicinity of their complementarity determining regions. Similarly, epitopes represent fuzzy binding sites, which are also characterized by local structural flexibility. Existing data suggest that the efficient interactions between antigens and antibodies rely on the conformational mobility and some disorder of their binding sites and therefore can be relatively well described by the "flexible lock - adjustable key" model, whereas both, extreme order (rigid lock-and-key) and extreme disorder (viral shape-shifters) are not compatible with the efficient antigen-antibody interactions and are not present in immune interactions.

The focus of this review is the human de novo purine biosynthetic pathway. The pathway enzymes are enumerated, as well as the reactions they catalyze and their physical properties. Early literature evidence suggested that they might assemble into a multi-enzyme complex called a metabolon. The finding that fluorescently-tagged chimeras of the pathway enzymes form discrete puncta, now called purinosomes, is further elaborated in this review to include: a discussion of their assembly; the role of ancillary proteins; their locus at the microtubule/mitochondria interface; the elucidation that at endogenous levels, purinosomes function to channel intermediates from phosphoribosyl pyrophosphate to AMP and GMP; and the evidence for the purinosomes to exist as a protein condensate. The review concludes with a consideration of probable signaling pathways that might promote the assembly and disassembly of the purinosome, in particular the identification of candidate kinases given the extensive phosphorylation of the enzymes. These collective findings substantiate our current view of the de novo purine biosynthetic metabolon whose properties will be representative of how other metabolic pathways might be organized for their function.