rDNA Instability and SIRT7 in Cellular Senescence

As the research and development community devotes ever greater resources to the development of senolytic rejuvenation therapies based on selective destruction of senescent cells, further exploration of the biochemistry of senescence continues apace. In this example, researchers find that the sirtuin SIRT7 has a role in suppressing cellular senescence that results from certain forms of DNA damage, and speculate that this might explain some of the reports linking SIRT7 activity to aging. As such an early stage of investigation, it is hard to say whether this will become relevant to some form of therapy, however.

Cellular senescence is a state of permanent cell cycle arrest that is induced by diverse types of stress associated with oncogene activation, DNA damage, or chromatin deregulation and can have tumor-suppressive effects. However, senescent cells also have profound deleterious effects that enhance tumor malignancy or contribute to tissue dysfunction in aging and disease. Indeed, senescent cells undergo dramatic alterations in metabolic and gene expression profiles with acquisition of a senescence-associated secretory phenotype (SASP). Through the SASP, even relatively low levels of senescent cells can have far-ranging effects that influence tissue function.

In the human genome, ribosomal DNA (rDNA) genes comprise ∼350 copies distributed in large clusters. As in yeast, mammalian rDNA genes are prone to instability, and recombination among repeats can lead to expansions, contractions, or translocations. Thus, maintaining rDNA stability is a serious challenge for genome integrity, and rDNA instability is a potential driving force of genomic instability in cancer.

In mammals, there are seven sirtuins, and a growing body of work has implicated these enzymes in protecting against diverse aging-related pathologic states from cancer to metabolic and neurodegenerative diseases. SIRT7 is the only mammalian sirtuin that is concentrated in nucleoli, subnuclear compartments where rDNA genes are located, and early studies found that SIRT7 binds rDNA regulatory sequences. Surprisingly, however, SIRT7 was found to stimulate rather than repress rDNA transcription. Recent work has also implicated SIRT7 in various aspects of DNA double strand break (DSB) repair and DNA damage signaling. However, no studies have examined potential effects of SIRT7 on nucleolar DSBs at rDNA loci.

Several reports have now implicated SIRT7 in regulation of mammalian aging. Decreased SIRT7 expression is observed in certain tissues with aging, and loss of SIRT7 in mice leads to shortened lifespan. However, much remains to be learned about the underlying molecular mechanisms through which SIRT7 influences aging pathology. Here, we report a novel role of human SIRT7 in protecting against cellular senescence by maintaining heterochromatin silencing and genomic stability at ribosomal DNA gene clusters. Our findings provide the first demonstration that rDNA instability has a causal role in triggering acute senescence of primary human cells and show that SIRT7-dependent heterochromatin silencing is a key mechanism protecting against this process.

Link: https://doi.org/10.1074/jbc.AC118.003325


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