Annual review of genetics最新文献

In bacteria, transcription and translation take place in the same cellular compartment. Therefore, a messenger RNA can be translated as it is being transcribed, a process known as transcription-translation coupling. This process was already recognized at the dawn of molecular biology, yet the interplay between the two key players, the RNA polymerase and ribosome, remains elusive. Genetic data indicate that an RNA sequence can be translated shortly after it has been transcribed. The closer both processes are in time, the less accessible the RNA sequence is between the RNA polymerase and ribosome. This temporal coupling has important consequences for gene regulation. Biochemical and structural studies have detailed several complexes between the RNA polymerase and ribosome. The in vivo relevance of this physical coupling has not been formally demonstrated. We discuss how both temporal and physical coupling may mesh to produce the phenomenon we know as transcription-translation coupling.

Spermatogenesis is a complex differentiation process coordinated spatiotemporally across and along seminiferous tubules. Cellular heterogeneity has made it challenging to obtain stage-specific molecular profiles of germ and somatic cells using bulk transcriptomic analyses. This has limited our ability to understand regulation of spermatogenesis and to integrate knowledge from model organisms to humans. The recent advancement of single-cell RNA-sequencing (scRNA-seq) technologies provides insights into the cell type diversity and molecular signatures in the testis. Fine-grained cell atlases of the testis contain both known and novel cell types and define the functional states along the germ cell developmental trajectory in many species. These atlases provide a reference system for integrated interspecies comparisons to discover mechanistic parallels and to enable future studies. Despite recent advances, we currently lack high-resolution data to probe germ cell-somatic cell interactions in the tissue environment, but the use of highly multiplexed spatial analysis technologies has begun to resolve this problem. Taken together, recent single-cell studies provide an improvedunderstanding of gametogenesis to examine underlying causes of infertility and enable the development of new therapeutic interventions.

Though cell size varies between different cells and across species, the nuclear-to-cytoplasmic (N/C) ratio is largely maintained across species and within cell types. A cell maintains a relatively constant N/C ratio by coupling DNA content, nuclear size, and cell size. We explore how cells couple cell division and growth to DNA content. In some cases, cells use DNA as a molecular yardstick to control the availability of cell cycle regulators. In other cases, DNA sets a limit for biosynthetic capacity. Developmentally programmed variations in the N/C ratio for a given cell type suggest that a specific N/C ratio is required to respond to given physiological demands. Recent observations connecting decreased N/C ratios with cellular senescence indicate that maintaining the proper N/C ratio is essential for proper cellular functioning. Together, these findings suggest a causative, not simply correlative, role for the N/C ratio in regulating cell growth and cell cycle progression.

Kinetochores are molecular machines that power chromosome segregation during the mitotic and meiotic cell divisions of all eukaryotes. Aristotle explains how we think we have knowledge of a thing only when we have grasped its cause. In our case, to gain understanding of the kinetochore, the four causes correspond to questions that we must ask: (a) What are the constituent parts, (b) how does it assemble, (c) what is the structure and arrangement, and (d) what is the function? Here we outline the current blueprint for the assembly of a kinetochore, how functions are mapped onto this architecture, and how this is shaped by the underlying pericentromeric chromatin. The view of the kinetochore that we present is possible because an almost complete parts list of the kinetochore is now available alongside recent advances using in vitro reconstitution, structural biology, and genomics. In many organisms, each kinetochore binds to multiple microtubules, and we propose a model for how this ensemble-level architecture is organized, drawing on key insights from the simple one microtubule-one kinetochore setup in budding yeast and innovations that enable meiotic chromosome segregation.

Meiosis, a key process in the creation of haploid gametes, is a complex cellular division incorporating unique timing and intricate chromosome dynamics. Abnormalities in this elaborate dance can lead to the production of aneuploid gametes, i.e., eggs containing an incorrect number of chromosomes, many of which cannot generate a viable pregnancy. For many decades, research has been attempting to address why this process is notoriously error prone in humans compared to many other organisms. Rapidly developing technologies, access to new clinical material, and a mounting public infertility crisis have kept the field both active and quickly evolving. In this review, we discuss the history of aneuploidy in humans with a focus on its origins in maternal meiosis. We also gather current working mechanistic hypotheses, as well as up-and-coming areas of interest that point to future scientific avenues and their potential clinical applications.

Autophagy, a lysosome-mediated degradation process evolutionarily conserved from yeast to mammals, is essential for maintaining cellular homeostasis and combating diverse cellular stresses. Autophagy involves de novo synthesis of a double-membrane autophagosome, sequestration of selected cellular contents, and subsequent delivery of sequestrated contents to the vacuole (in yeasts and plants) or to lysosomes (in animal cells) for degradation and recycling. Genetic studies in unicellular and multicellular model organisms have systematically revealed the molecular machinery, regulation, and function of autophagy in physiological settings. I review genetic studies in model organisms-from yeast to worm to fly-that enable us to not only identify autophagy genes, including ATG genes and the metazoan-specific EPG genes, but also uncover variants of autophagy in developmental contexts, novel regulatory mechanisms, and signaling events involved in mediating systemic autophagy response. Genetic analysis also helps us understand the liquid-liquid phase separation and transition that control autophagic degradation of protein aggregates. The emerging role of autophagy in zebrafish tissue regeneration is also discussed.

Various stem cells in the body are tasked with maintaining tissue homeostasis throughout the life of an organism and thus must be resilient to intrinsic and extrinsic challenges such as infection and injury. Crucial to these challenges is genome maintenance because a high mutational load and persistent DNA lesions impact the production of essential gene products at proper levels and compromise optimal stem cell renewal and differentiation. Genome maintenance requires a robust and well-regulated DNA damage response suited to maintaining specific niches and tissues. In this review, we explore the similarities and differences between diverse stem cell types derived from (or preceding) all germ layers, including extraembryonic tissues. These cells utilize different strategies, including implementation of robust repair mechanisms, modulation of cell cycle checkpoints best suited to eliminating compromised cells, minimization of cell divisions, and differentiation in response to excessive damage.

The discovery of biased histone inheritance in asymmetrically dividing Drosophila melanogaster male germline stem cells demonstrates one means to produce two distinct daughter cells with identical genetic material. This inspired further studies in different systems, which revealed that this phenomenon may be a widespread mechanism to introduce cellular diversity. While the extent of asymmetric histone inheritance could vary among systems, this phenomenon is proposed to occur in three steps: first, establishment of histone asymmetry between sister chromatids during DNA replication; second, recognition of sister chromatids carrying asymmetric histone information during mitosis; and third, execution of this asymmetry in the resulting daughter cells. By compiling the current knowledge from diverse eukaryotic systems, this review comprehensively details and compares known chromatin factors, mitotic machinery components, and cell cycle regulators that may contribute to each of these three steps. Also discussed are potential mechanisms that introduce and regulate variable histone inheritance modes and how these different modes may contribute to cell fate decisions in multicellular organisms.

The initiation, progression, and relapse of cancers often result from mutations occurring within somatic cells. Consequently, processes that elevate mutation rates accelerate carcinogenesis and hinder the development of long-lasting therapeutics. Recent sequencing of human cancer genomes has identified patterns of mutations, termed mutation signatures, many of which correspond to specific environmentally induced and endogenous mutation processes. Some of the most frequently observed mutation signatures are caused by dysregulated activity of APOBECs, which deaminate cytidines in single-stranded DNA at specific sequence motifs causing C-to-T and C-to-G substitutions. In humans, APOBEC-generated genetic heterogeneity in tumor cells contributes to carcinogenesis, metastasis, and resistance to therapeutics. Here, we review the current understanding of APOBECs' role in cancer mutagenesis and impact on disease and the biological processes that influence APOBEC mutagenic capacity.

Within the life cycle of a living organism, another life cycle exists for the selfish genome inhabitants, which are called transposable elements (TEs). These mobile sequences invade, duplicate, amplify, and diversify within a genome, increasing the genome's size and generating new mutations. Cells act to defend their genome, but rather than permanently destroying TEs, they use chromatin-level repression and epigenetic inheritance to silence TE activity. This level of silencing is ephemeral and reversible, leading to a dynamic equilibrium between TE suppression and reactivation within a host genome. The coexistence of the TE and host genome can also lead to the domestication of the TE to serve in host genome evolution and function. In this review, we describe the life cycle of a TE, with emphasis on how epigenetic regulation is harnessed to control TEs for host genome stability and innovation.