Annual Review of Genetics

We have made rapid progress in recent years in identifying the genetic causes of many human diseases. However, despite this recent progress, our mechanistic understanding of these diseases is often incomplete. This is a problem because it limits our ability to develop effective disease treatments. To overcome this limitation, we need new concepts to describe and comprehend the complex mechanisms underlying human diseases. Condensate formation by phase separation emerges as a new principle to explain the organization of living cells. In this review, we present emerging evidence that aberrant forms of condensates are associated with many human diseases, including cancer, neurodegeneration, and infectious diseases. We examine disease mechanisms driven by aberrant condensates, and we point out opportunities for therapeutic interventions. We conclude that phase separation provides a useful new framework to understand and fight some of the most severe human diseases.

This review focuses on mutations of mitochondrial DNA (mtDNA) which are an important cause of mitochondrial disorders in humans and are also associated with common neurodegenerative disorders and aging. The high copy number of mtDNA and its maternal transmission make the inheritance of mtDNA mutations fundamentally different from the Mendelian inheritance of nuclear DNA mutations. There is often a mixture of wild-type and mutated mtDNAs (heteroplasmy), and heterogeneity in the distribution of mutated mtDNAs is one plausible explanation for the widely varying phenotypes in patients with mitochondrial disorders. The application of molecular genetics has led to significant progress in the studies of human mitochondrial disorders in the past decade. Future studies including the development of animal models are needed to advance our understanding of the pathogenesis of mitochondrial disorders to enable, in tum, the development of novel therapies and genetic rescue strategies for the treatment of human disease.

▪ Abstract  The endoplasmic reticulum (ER) serves as a way-station during the biogenesis of nearly all secreted proteins, and associated with or housed within the ER are factors required to catalyze their import into the ER and facilitate their folding. To ensure that only properly folded proteins are secreted and to temper the effects of cellular stress, the ER can target aberrant proteins for degradation and/or adapt to the accumulation of misfolded proteins. Molecular chaperones play critical roles in each of these phenomena.

The myriad developmental roles served by the T-box family of transcription factor genes defy easy categorization. Present in all metazoans, the T-box genes are involved in early embryonic cell fate decisions, regulation of the development of extraembryonic structures, embryonic patterning, and many aspects of organogenesis. They are unusual in displaying dosage sensitivity in most instances. In humans, mutations in T-box genes are responsible for developmental dysmorphic syndromes, and several T-box genes have been implicated in neoplastic processes. T-box transcription factors function in many different signaling pathways, notably bone morphogenetic protein and fibroblast growth factor pathways. The few downstream target genes that have been identified indicate a wide range of downstream effectors.

▪ Abstract  Eubacterial plasmids and chromosomes encode multiple killer genes belonging to the hok gene family. The plasmid-encoded killer genes mediate plasmid stabilization by killing plasmid-free cells. This review describes the genetics, molecular biology, and evolution of the hok gene family. The complicated antisense RNA-regulated control-loop that regulates posttranscriptional and postsegregational activation of killer mRNA translation in plasmid-free cells is described in detail. Nucleotide covariations in the mRNAs reveal metastable stem-loop structures that are formed at the mRNA 5′ ends in the nascent transcripts. The metastable structures prevent translation and antisense RNA binding during transcription. Coupled nucleotide covariations provide evidence for a phylogenetically conserved mRNA folding pathway that involves sequential dynamic RNA rearrangements. Our analyses have elucidated an intricate mechanism by which translation of an antisense RNA-regulated mRNA can be conditionally activated. The complex phylogenetic relationships of the plasmid- and chromosome-encoded systems are also presented and discussed.

Các gãy đôi chuỗi DNA (DSBs) là những tổn thương tế bào có thể gây ra các sự kiện đột biến hoặc chết tế bào nếu không được sửa chữa hoặc được sửa chữa một cách không thích hợp. Tế bào sử dụng hai con đường chính để sửa chữa DSB: nối đầu không tương đồng (NHEJ) và tái tổ hợp đồng di truyền (HR). Sự lựa chọn giữa các con đường này phụ thuộc vào giai đoạn của chu kỳ tế bào và bản chất của các đầu DSB. Một yếu tố quyết định quan trọng trong việc lựa chọn đường sửa chữa là khởi đầu của việc cắt ngắn đầu DNA theo hướng 5′-3′, điều này cam kết tế bào vào sửa chữa phụ thuộc vào sự tương đồng, và ngăn cản sửa chữa bằng NHEJ cổ điển. Tại đây, chúng tôi xem xét các thành phần của cơ chế cắt đầu, vai trò của cấu trúc đầu, và giai đoạn chu kỳ tế bào trong quá trình cắt ngắn, cũng như mối tương tác giữa xử lý các đầu với NHEJ.