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The nuclear envelope in genome organization, expression and stability

Key Points

  • DNA is non-randomly arranged in the nucleus, with silent chromatin domains preferentially associating with inner nuclear membrane proteins and lamins in yeast and larger eukaryotes, respectively.

  • Nuclear pore complexes, which are preferentially linked to actively transcribed genes in Saccharomyces cerevisiae, may have a more complex role in gene expression in larger eukaryotes.

  • Studies conducted mainly in S. cerevisiae suggest that inner nuclear membrane proteins and nuclear pore complexes may have multiple roles in maintaining genome stability, including the suppression of aberrant recombination and rescue of collapsed replication forks.

  • Chromosomal domains can be stabilized by inner nuclear membrane proteins in natural settings but nucleoplasmic or internal DNA loci may be targeted to the nuclear pore for DNA repair.

  • Interactions between proteins of the inner and outer nuclear membrane link chromatin to cytoskeletal dynamics and have a role in meiotic chromosome pairing.

Abstract

Non-random positioning of chromosomal domains relative to each other and to nuclear landmarks is a common feature of eukaryotic genomes. In particular, the distribution of DNA loci relative to the nuclear periphery has been linked to both transcriptional activation and repression. Nuclear pores and other integral membrane protein complexes are key players in the dynamic organization of the genome in the nucleus, and recent advances in our understanding of the molecular networks that organize genomes at the nuclear periphery point to a further role for non-random locus positioning in DNA repair, recombination and stability.

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Figure 1: The nuclear periphery and gene expression.
Figure 2: The nuclear envelope in gene expression and protection of repetitive DNA sequences.
Figure 3: Perinuclear interactions stabilize a genome.
Figure 4: Transmembrane coupling of chromatin to the cytoskeleton during the mitotic and meiotic cell cycle.
Figure 5: Perinuclear tethering and global genome organization.

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Acknowledgements

We thank J.N.Y. Chan and other members of our laboratories for discussions and comments. K.M. is supported by the Canadian Institutes of Health Research (CIHR) Institute of Aging and the CIHR Institute of Genetics Lap-Chee Tsui Award. D.M. is supported by the National Institutes of Health (NIH) and is an investigator of the Howard Hughes Medical Institute (HHMI).

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Glossary

Nucleolus

A nuclear compartment that is home to genes encoding rRNA and is the site of most ribosome manufacturing steps.

Telomere

A segment at the end of each chromosome arm that consists of repetitive sequences and prevents the normal chromosome ends from being recognized as DSBs.

Centromere

A specialized region on a chromosome that is composed of highly condensed heterochromatin and is the platform for the assembly of kinetochores.

Intermediate filament protein

A member of a large family of cytoplasmic and nuclear proteins that polymerize into stable filaments of 10 nm in diameter.

Muscular dystrophies

A group of diseases characterized by the gradual loss of muscle structure and function. These diseases can be caused by mutations affecting various proteins, including lamins and INM proteins.

Laminopathies

A group of diseases that include premature ageing syndromes and certain types of muscular dystrophies and are associated with mutations in genes encoding lamins.

DamID

A technology that identifies the DNA sites with which a protein interacts by fusing the protein to an adenine methyltransferase. This allows for site identification by detection of the foreign adenosine methylation mark across the genome.

Insulator protein

A protein that binds an insulator element, which is a genetic boundary element that can block enhancers.

Histone deacetylase

An enzyme that removes post-translational acetylation marks from amino acids on the tails of histone proteins.

Heterochromatin

A genomic region characterized by a compact form of chromatin that makes the DNA less accessible to the protein factors that usually bind.

B-type lamin

One of a group of proteins that include the ubiquitously expressed lamin B1 and lamin B2, which are encoded by the LMNB1 and LMNB2 genes, respectively.

RENT

A protein complex that ensures silent chromatin assembly at the intergenic spacers of ribosomal DNA, maintains the stability of ribosomal DNA repeats and prevents premature exit from the cell cycle.

Cohibin

A protein complex that maintains the stability of rDNA repeats by ensuring silent chromatin assembly and attachment to the nuclear periphery.

CLIP

A complex of INM proteins that maintains the stability of ribosomal DNA repeats by anchoring them to the nuclear envelope.

Emery–Dreifuss muscular dystrophy

A disease that is characterized by muscle wasting and cardiac defects and is associated with mutations in genes encoding lamins or the LEM domain protein emerin.

Telomerase

An enzyme that uses its own RNA subunit as a template to catalyse the lengthening of telomeres following replication.

Non-homologous end joining

A pathway that repairs DNA DSBs by directly ligating the broken ends, without the need for a homologous template.

A-type lamin

One of a group of lamins that are primarily expressed after the gastrulation stage of development. This class includes the splice variants lamin A and lamin C, which are encoded by the LMNA gene.

Facio-scapulo-humeral muscular dystrophy

A common form of muscular dystrophy that is characterized by the progressive weakening or loss of skeletal muscles. Common locations of these weaknesses at disease onset are the face (facio), shoulder (scapulo) and upper arms (humeral).

Synthetic lethal

A genetic interaction in which the deletion of two genes at the same time results in lethality. An organism in which one gene is deleted and the other gene is present will still be viable.

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Mekhail, K., Moazed, D. The nuclear envelope in genome organization, expression and stability. Nat Rev Mol Cell Biol 11, 317–328 (2010). https://doi.org/10.1038/nrm2894

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