Epigenetic regulation of genome integrity by a prion-based mechanism

2018

DNA Repair

Self Cite

From bacteria to humans, ancient stress responses enable organisms to contend with damage to both the genome and the proteome. These pathways have long been viewed as fundamentally separate responses. Yet recent discoveries from multiple fields have revealed surprising links between the two. Many DNA-damaging agents also target proteins, and mutagenesis induced by DNA damage produces variant proteins that are prone to misfolding, degradation, and aggregation. Likewise, recent studies have observed pervasive engagement of a p53-mediated response, and other factors linked to maintenance of genomic integrity, in response to misfolded protein stress. Perhaps most remarkably, protein aggregation and self-assembly has now been observed in multiple proteins that regulate the DNA damage response. The importance of these connections is highlighted by disease models of both cancer and neurodegeneration, in which compromised DNA repair machinery leads to profound defects in protein quality control, and vice versa.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutations, protein homeostasis, and epigenetic control of genome integrity

Xie

2018

DNA Repair

Self Cite

“…These classes of proteins are uniquely suited to precipitate large phenotypic changes, as they can proximally affect the abundance of large numbers of other cellular components. Several other proteins identified as prion-like also belong to functional classes that might be expected to potentiate pleiotropic effects, such as chromatin remodelers [10,36] and DNA repair enzymes [52]. The rate of switching into the [ PRION + ] state can be modulated by a wide array of inputs, including missense mutations [53], alternative splicing isoforms [26], post-translational modifications [28], changes in protein abundance [54], and external conditions [38,44].…”

Section: Prion-like Assembly From the Systems Biology Perspectivementioning

confidence: 99%

Organizing biochemistry in space and time using prion-like self-assembly

Jakobson

Current Opinion in Systems Biology

2018

Self Cite

Prion-like proteins have the capacity to adopt multiple stable conformations, at least one of which can recruit proteins from the native conformation into the alternative fold. Although classically associated with disease, prion-like assembly has recently been proposed to organize a range of normal biochemical processes in space and time. Organisms from bacteria to mammals use prion-like mechanisms to (re)organize their proteome in response to intracellular and extracellular stimuli. Prion-like behavior is an economical means to control biochemistry and gene regulation at the systems level, and prions can act as protein-based genes to facilitate quasi-Lamarckian inheritance of induced traits. These mechanisms allow individual cells to express distinct heritable traits using the same complement of polypeptides. Understanding and controlling prion-like behavior is therefore a promising strategy to combat diverse pathologies and organize engineered biological systems.

What Has a Century of Quantitative Genetics Taught Us About Nature's Genetic Tool Kit?

Jakobson

2020

Annu. Rev. Genet.

The complexity of heredity has been appreciated for decades: Many traits are controlled not by a single genetic locus but instead by polymorphisms throughout the genome. The importance of complex traits in biology and medicine has motivated diverse approaches to understanding their detailed genetic bases. Here, we focus on recent systematic studies, many in budding yeast, which have revealed that large numbers of all kinds of molecular variation, from noncoding to synonymous variants, can make significant contributions to phenotype. Variants can affect different traits in opposing directions, and their contributions can be modified by both the environment and the epigenetic state of the cell. The integration of prospective (synthesizing and analyzing variants) and retrospective (examining standing variation) approaches promises to reveal how natural selection shapes quantitative traits. Only by comprehensively understanding nature's genetic tool kit can we predict how phenotypes arise from the complex ensembles of genetic variants in living organisms. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.