Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction

Cellular senescence can also start during the G2 phase in response to telomere damage, DNA damage, or oncogene activation.

“Although traditionally described as an irreversible form of G1 arrest, cellular senescence can also start during the G2 phase in response to telomere damage [57], DNA damage [58], or oncogene activation [59].”

G2 and G1, for cells with 4N DNA content after mitosis by-pass, might be the phases at which senescent cells exit the cell cycle upon acute and robust DNA damage that induces a rapid cell response, typically within 24 h.

“Therefore, G2 and G1 (for cells with 4N DNA content after mitosis by-pass) might be the phases at which senescent cells exit the cell cycle upon acute and robust DNA damage that induces a rapid cell response, typically within 24 h [58,59].”

When this mechanism fails, cells that are long-term arrested in G2 can enter a permanent G1-like state without going through mitosis, thereby generating tetraploid cells.

“When this mechanism fails, cells that are long-term arrested in G2 can enter a permanent G1-like state without going through mitosis (mitosis by-pass), thereby generating tetraploid cells [59] (Figure 1).”

Mitotic by-pass, which results from insufficient levels of mitotic proteins, is sufficient and necessary for OIS both in vitro and in vivo.

“Most notably mitotic by-pass, which results from insufficient levels of mitotic proteins, is sufficient and necessary for OIS both in vitro and in vivo [59].”

Replicative senescence or various senescence-causing stimuli induce p53-dependent mitotic bypass, irreversible arrest in 4N G1, and accumulation of p16 and beta-galactosidase.

“The Nakanishi group showed that replicative senescence or exposure to various senescence-causing stimuli induces p53-dependent mitotic bypass (referred to as mitotic skipping), entailing irreversible cell cycle arrest in the 4N G1 state and accumulation of the senescent markers p16 and b-galactosidase.93”

APC/C-Cdh1 activation alone is not sufficient to induce senescence; repression of mitotic regulators by pRb family pocket proteins is also required.

“However, unlike p53-mediated mitotic bypass, APC/C Cdh1 activation alone does not appear to be sufficient to induce senescence, that additionally requires repression of mitotic regulators by pRb family pocket proteins (Fig. 2).”

p21 depletion prevents senescence less efficiently than p53 depletion.

“Moreover, p21 depletion prevents senescence less efficiently than p53 depletion, prompting the authors to suggest that p53 might activate the pRb family independently of p21 (Fig. 5G in ref. 93 ).”

Transient p53 induction in G2, but not G1, is sufficient to induce mitotic bypass and senescence; this is not true for p21.

“While the previously discussed works 93,95 show that transient induction of p53 in G2 (but not in G1) is sufficient to induce mitotic bypass and senescence, this is not the case for p21.93”

Cell cycle exit in p21-deficient cells is associated with p16 accumulation.

“In addition to a previous report, 48 this alternative possibility is also supported by data showing that cell cycle exit in p21deficient cells is associated with p16 accumulation (Figure S3B in ref. 93 ).”

Transient Chk1/2 activation from partial TRF2 depletion or acute DNA damage, when p21 induction is inefficient, can delay but not prevent mitosis.

“Conversely, transient Chk1/2 activation, induced by partial TRF2 depletion 83 or acute DNA damage (by IR), 93 in the absence of (efficient) p21 induction can transiently delay, but not prevent mitosis.”

These cells then progress into mitosis and eventually die.

“In the absence of sustained Chk1/2 activation, p53/p21-deficient cells exposed to genotoxic agents arrest only transiently in G2 and then progress into mitosis and eventually die.59,93”

Without prolonged Chk1/2 activation, cells lacking p53 and p21 that are exposed to DNA-damaging agents arrest in G2 only briefly.

“In the absence of sustained Chk1/2 activation, p53/p21-deficient cells exposed to genotoxic agents arrest only transiently in G2 and then progress into mitosis and eventually die.59,93”

p21 levels may decrease in 'late' senescence or when senescence has been achieved, whereas high levels of p16 are thought to be maintained throughout senescence.

“p21 levels may also decrease in ‘late’ senescence or when senescence has been achieved [115,158], whereas high levels of p16 are thought to be maintained throughout senescence [158,159].”