Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

Abstract

Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells.

Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence

“…At this time, it is unclear why there is such a specific activation of the cholesterol biosynthesis pathway by shLSG1 and why this signature is also so prevalent in OIS and other forms of senescence. A recent study identified accumulation of the ribosomal 40S subunit protein RPS14 as a mechanism contributing to senescence in response to multiple stimuli (Lessard et al, 2018). Unlike our p53-dependent response, the response to RPS14 was Rb-dependent, indicating that it is mechanistically distinct.…”

Ribosomal stress-induced senescence as a novel pro-senescence strategy for p16 positive basal-like breast cancer

“…It has also been suggested that dysregulation of RPs supports the hyperproliferative cancer cell phenotype 21 compounds suggests that tumour cell addiction to enhanced ribosomal biosynthesis could be exploited for therapeutic gain, and our findings indicate that this could be achieved through a RSIS pro-senescence strategy. Both our work and the findings of Lessard et al 16 indicate that a small molecule which perturbs ribosomal protein homeostasis could be effective at selectively engaging a p16-dependent senescence programme in cancer cells. In support of this, we present evidence of co-ordinated dysregulation of our two most potent RP hits, RPS3A and RPS7.…”

“…contribute to cell cycle arrest through the Rb pathway which is associated with altered nucleolar morphology 16 . In summary, we show that RP knockdown initiates a p16-mediated senescence programme in a p53-independent and cancer-specific manner, and paves the way for pro-senescence therapies aimed at re-engaging this potent tumour suppressor mechanism in highly aggressive breast cancer subtypes, such as BLBC.…”

Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

“…It should also be mentioned that senescence of tumor cells lacking functional cell cycle inhibitors may be explained by defects in senescence-associated ribosome biogenesis and concomitant accumulation of rRNA precursors and ribosomal proteins. From the mechanistic point of view, senescent cells accumulate the ribosomal protein S14 (RPS14 or uS11) in the soluble non-ribosomal compartment, where it binds and inhibits cyclin-dependent kinase 4, leading to the inhibition of retinoblastoma protein phosphorylation, cell cycle arrest, and senescence [127].…”