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[
Trends Genet,
2002]
Huntington''s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HD gene. The expanded repeats are translated into an abnormally long polyglutamine tract close to the N-terminus of the HD gene product, huntingtin. Studies in mouse models and human suggest that the mutation is associated with a deleterious gain of function. There is now a wide range of mouse models for HD, providing important insights into processes associated with disease pathogenesis. These models have been complemented by studies in Drosophila and Caenorhabditis elegans that have allowed the identification of possible modifier loci through suppressor screens.
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[
Curr Opin Genet Dev,
2016]
In many species, male and female animals differ in the number of X chromosomes they possess. As a consequence, large scale differences in gene dosage exist between sexes; a phenomenon that is rarely tolerated by the organism for changes in autosome dosage. Several strategies have evolved independently to balance X-linked gene dosage between sexes, named dosage compensation (DC). The molecular basis of DC differs among the three best-studied examples: mammals, fruit fly and nematodes. In this short review, we summarize recent microscopic and chromosome conformation capture data that reveal key features of the compensated X chromosome and highlight the events leading to the establishment of a functional, specialized nuclear compartment, the X domain.
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[
Epigenetics,
2009]
Dosage compensation is an essential process that equalizes X-linked gene dosage between the sexes. In the worm Caenorhabditis elegans, a complex of proteins called the dosage compensation complex (DCC) binds both X chromosomes in hermaphrodites to downregulate gene expression two-fold and hence to reduce X-linked gene expression levels equal to that in males. Five subunits of the DCC form the condensin I(DC) complex, a homolog of the evolutionarily conserved condensin complex required for chromosome segregation and compaction during mitosis and meiosis. How related complexes can perform such diverse functions remains a mystery. Nevertheless, it is believed that the mitotic and interphase functions of condensin are mechanistically related and understanding one process will reveal new insights into the other. We discuss how during worm dosage compensation a condensin-mediated function may guide the organization of the interphase chromatin fibers, leading to the formation of a repressive nuclear compartment.
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[
Front Genet,
2014]
In many organisms sexual fate is determined by a chromosome-based method which entails a difference in sex chromosome-linked gene dosage. Consequently, a gene regulatory mechanism called dosage compensation equalizes X-linked gene expression between the sexes. Dosage compensation initiates as cells transition from pluripotency to differentiation. In Caenorhabditis elegans, dosage compensation is achieved by the dosage compensation complex (DCC) binding to both X chromosomes in hermaphrodites to downregulate gene expression by twofold. The DCC contains a subcomplex (condensin I(DC)) similar to the evolutionarily conserved condensin complexes which play a fundamental role in chromosome dynamics during mitosis. Therefore, mechanisms related to mitotic chromosome condensation are hypothesized to mediate dosage compensation. Consistent with this hypothesis, monomethylation of histone H4 lysine 20 is increased, whereas acetylation of histone H4 lysine 16 is decreased, both on mitotic chromosomes and on interphase dosage compensated X chromosomes in worms. These observations suggest that interphase dosage compensated X chromosomes maintain some characteristics associated with condensed mitotic chromosome. This chromosome state is stably propagated from one cell generation to the next. In this review we will speculate on how the biochemical activities of condensin can achieve both mitotic chromosome compaction and gene repression.
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Boya P, Baehrecke EH, Tavernarakis N, Yoshimori T, Cuervo AM, Fulda S, Choi AM, Scorrano L, Jaattela M, Gewirtz DA, Hansen M, Kimmelman AC, Tooze SA, Levine B, Simon HU, Kumar S, Deretic V, Debnath J, Juhasz G, Kraft C, Colombo MI, Dikic I, Martens S, Green DR, Mizushima N, Zhong Q, Kroemer G, Penninger JM, Codogno P, Munz C, Chu CT, Madeo F, Harper JW, Simon AK, Galluzzi L, Simonsen A, Cecconi F, Yue Z, Santambrogio L, Yuan J, Piacentini M, Bravo-San Pedro JM, Fimia GM, Martinez J, Eskelinen EL, Murphy LO, Ryan KM, Johansen T, Lopez-Otin C, Ballabio A, Rubinsztein DC, Ktistakis NT, Reggiori F, Melendez A
[
EMBO J,
2017]
Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.