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The role of nuclear architecture in genomic instability and ageing

Nature Reviews Molecular Cell Biology volume 8, pages 692–702 (2007)Cite this article

Key Points

  • Heterochromatin, euchromatin and the nuclear matrix are often collectively referred to as the nuclear architecture. Changes in nuclear architecture appear to be an evolutionarily conserved hallmark of ageing that may result in increased genomic instability as well as transcriptional deregulation.

  • In yeast, ageing is a direct consequence of increased genomic instability in ribosomal DNA (rDNA). The NAD+-dependent histone deacetylase Sir2 has a crucial role in heterochromatin formation in budding yeast by stabilizing rDNA and thereby extending lifespan.

  • DNA damage and increased rDNA instability trigger the redistribution of Sir2-containing DNA-silencing complexes from heterochromatin to sites of DNA damage. This results in a loss of silencing at functionally important loci — telomeres, rDNA and mating-type loci — and phenotypic changes such as sterility, which together are manifested as yeast ageing.

  • Human premature-ageing syndromes implicate increased genomic instability and alterations in nuclear architecture in normal human ageing. Cells from older humans and cells that have undergone DNA-damage-induced senescence show significant changes in heterochromatin, including loss of perinuclear heterochromatin and the formation of senescence-associated heterochromatin foci (SAHFs).

  • Changes in gene expression are a hallmark of ageing across species and may directly contribute to the ageing process by impairing the ability of a cell to function normally. Changes in nuclear architecture caused by DNA damage may underlie these changes.

  • Like in yeast, mammalian DNA-damage repair requires the recruitment of chromatin-modifying enzymes to sites of DNA damage. We propose that DNA damage triggers an evolutionarily conserved redistribution of chromatin modifiers that aids DNA repair but may result in loss of silencing at other loci, thereby explaining age-related gene-expression changes. We refer to this as the epigenetic balance hypothesis of ageing.

Abstract

Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time — a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA–protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms.

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Figure 1: Comparison of age-related changes in nuclear architecture between yeast and mammalian cells.
Figure 2: Redistribution of heterochromatin-associated factors as a cause of age-related changes in nuclear architecture and gene expression.

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Acknowledgements

We thank B. North for critical reading of the manuscript. The Sinclair laboratory is supported by National Institutes of Health grants and the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. P.O. is supported by the National Space Biomedical Research Institute.

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  1. Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts, USA

    Philipp Oberdoerffer & David A. Sinclair

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Correspondence to David A. Sinclair.

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David A. Sinclair is a co-founder of and consultant to Sirtris Pharmaceuticals, Inc. (USA), a company that aims to treat diseases by modulating sirtuins. He sits on the board of directors and scientific advisory board, and owns less than 1% equity.

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DATABASES

Entrez Gene

WRN

LMNA

ATM

OMIM

ataxia telangiectasia

Hutchinson–Gilford progeria syndrome

Werner syndrome

FURTHER INFORMATION

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Glossary

Senescence

A nearly irreversible stage of permanent G1 cell-cycle arrest, which is linked to morphological changes, metabolic changes and changes in gene expression. The induction of senescence depends on p53 and cell-cycle inhibitors such as p21 and p16.

Mating-type locus

The mating of yeast only occurs between haploids, which can be either mating type a or mating type α. The mating type is determined by a single locus (MAT). Gene conversion between MAT and the silent mating-type loci HML and HMR allows haploid yeast to switch to the active mating type as often as every cell cycle.

Telomeres

Regions of highly repetitive DNA at the ends of linear chromosomes. Telomeres function as caps to protect the DNA ends from degradation or fusion with other chromosomes, and as facilitators of DNA replication at the ends of chromosomes by recruiting the reverse transcriptase telomerase.

Progeroid disease

A genetic disorder in which various tissues, organs or systems of the human body appear to age prematurely. These diseases are often called segmental progeroid diseases because they do not fully recapitulate normal ageing. A common feature of such diseases is genomic instability.

RecQ DNA helicase

One of a family of DNA helicases that help to stabilize replication forks and remove DNA recombination intermediates, thereby maintaining genome integrity. In humans, there are five family members; mutations in three of these helicases are associated with a predisposition to cancer and premature ageing.

Position-effect variegation

The variation in gene expression that can occur between genetically identical cells when a gene is juxtaposed to a region of contracting and expanding heterochromatin.

Transcription-coupled repair

A DNA-repair mechanism that operates in tandem with transcription and involves members of the XP gene family. Failure of the transcription-coupled repair mechanism results in Cockayne syndrome, an extreme form of accelerated ageing that is fatal early in life.

Base-excision repair

(BER). A DNA-repair pathway that corrects single mutated bases. The two main enzymes used in BER are DNA glycosylases and apurinic or apyrimidinic (AP) endonucleases. The DNA glycosylase hydrolyses the glycosidic bond to create an AP site, which is then recognized and excised by the AP endonuclease, allowing DNA polymerases to replace the missing base.

Xeroderma pigmentosa

A genetic DNA-repair disorder in which the ability of the body to remove damage caused by ultraviolet light is impaired, leading to multiple basaliomas and other skin malignancies at a young age.

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Oberdoerffer, P., Sinclair, D. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol 8, 692–702 (2007). https://doi.org/10.1038/nrm2238

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