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How does cellular senescence affect gene expression?

Cellular senescence is a state of permanent cell cycle arrest that occurs in response to various stressors, such as DNA damage, telomere shortening, or oncogene activation. It is characterized by a distinct gene expression profile, which includes the upregulation of certain genes and the downregulation of others.

Upregulation of senescence-associated genes

During cellular senescence, there is a significant upregulation of genes that are commonly referred to as senescence-associated genes (SAGs). These genes play a crucial role in driving and maintaining the senescent phenotype. Some of the well-known SAGs include p16INK4a, p21CIP1/WAF1, and senescence-associated secretory phenotype (SASP) genes.

The upregulation of p16INK4a and p21CIP1/WAF1 leads to cell cycle arrest by inhibiting the activity of cyclin-dependent kinases (CDKs) and their associated cyclins. This prevents the cells from proliferating further and contributes to the irreversible growth arrest observed in senescent cells.

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The SASP genes are responsible for the secretion of various factors, including pro-inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases. The SASP plays a crucial role in the senescence-associated secretory phenotype, which can have both beneficial and detrimental effects on neighboring cells and tissues.

Downregulation of genes involved in cell proliferation and DNA repair

Conversely, cellular senescence is also associated with the downregulation of genes involved in cell proliferation and DNA repair. This downregulation further contributes to the irreversible growth arrest and impaired DNA repair capacity observed in senescent cells.

For example, genes involved in the cell cycle progression, such as cyclins and CDKs, are downregulated in senescent cells. This downregulation prevents the cells from re-entering the cell cycle and resuming proliferation.

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In addition, genes involved in DNA repair mechanisms, such as DNA damage response genes and DNA repair enzymes, are also downregulated in senescent cells. This compromises the ability of senescent cells to repair DNA damage, leading to the accumulation of DNA lesions and genomic instability.

Epigenetic changes and altered gene expression

Cellular senescence is also associated with significant epigenetic changes, which can further influence gene expression patterns. These epigenetic changes include alterations in DNA methylation patterns, histone modifications, and chromatin remodeling.

For example, the promoter regions of certain genes may become hypermethylated during senescence, leading to their transcriptional repression. Conversely, other genes may undergo hypomethylation, resulting in their upregulation.

In addition, senescence-associated histone modifications, such as increased levels of H3K9me3 and H4K20me3, can also contribute to the transcriptional repression of specific genes.

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Overall, cellular senescence profoundly affects gene expression patterns through the upregulation of senescence-associated genes, the downregulation of genes involved in cell proliferation and DNA repair, and epigenetic changes. These changes contribute to the senescent phenotype and have implications for aging and age-related diseases.

Keywords: senescence, associated, senescent, repair, cellular, upregulation, downregulation, expression, involved