Polycomb CBX7 has a unifying role in cellular lifespan

Abstract

In contrast to cancer cells and embryonic stem cells, the lifespan of primary human cells is finite. After a defined number of population doublings, cells enter in an irreversible growth-arrested state termed replicative senescence. Mutations of genes involved in immortalization can contribute to cancer. In a genetic screen for cDNAs bypassing replicative senescence of normal human prostate epithelial cells (HPrEC), we identified CBX7, a gene that encodes a Polycomb protein, as shown by sequence homology, its interaction with Ring1 and its localization to nuclear Polycomb bodies. CBX7 extends the lifespan of a wide range of normal human cells and immortalizes mouse fibroblasts by downregulating expression of the Ink4a/Arf locus. CBX7 does not inter-function or colocalize with Bmi1, and both can exert their actions independently of each other as shown by reverse genetics. CBX7 expression is downregulated during replicative senescence and its ablation by short-hairpin RNA (shRNA) treatment inhibited growth of normal cells though induction of the Ink4a/Arf locus. Taken together, these data show that CBX7 controls cellular lifespan through regulation of both the p16(Ink4a)/Rb and the Arf/p53 pathways.

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

“…In normal human diploid fibroblast WI-38 cells, NUAK1 is suggested to regulate senescence by a mechanism that does not involve p53 (Humbert et al, 2010), which is not consistent with our findings for p53 and p21/WAF1 in A549 or G361 cells and also conflicts with earlier reports that have suggested that the p53 pathway is involved in regulation of senescence in normal human cells (Gil et al, 2004;Herbig et al, 2004). Results from Humbert et al (2010) also have shown that, depending on the cell type, the aneuploidy induced by NUAK1 might have different consequences: senescence or cell death.…”

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…Much less is known about how the function and expression of the PRCs and their components are controlled. The regulation of CBX7 is particularly interesting because CBX7 is implicated in senescence (Gil et al ., 2004) and cancer (Bernard et al ., 2005; Scott et al ., 2007; Pallante et al ., 2008; Karamitopoulou et al ., 2010). In addition, CBX7 levels and consequently the composition of PRC1 complexes change dramatically during ES cell differentiation (Morey et al ., 2012; O'Loghlen et al ., 2012).…”

“…As a component of PRC1, CBX7 represses the INK4/ARF locus (Gil & O'Loghlen, 2014). Indeed, CBX7 was first identified in a screen for bypass of replicative senescence (Gil et al ., 2004). More recently, CBX7 was recognized as the main orthologue of Drosophila Polycomb implicated in maintaining the self‐renewal of embryonic stem (ES) cells (Morey et al ., 2012; O'Loghlen et al ., 2012).…”

Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

“…The pRB pathway is also activated by upregulation of p16INK4a. The mechanism by which expression of p16INK4a is increased is not known, although it is likely to involve regulation of polycomb proteins that repress expression of p16INK4a (11,47,62).…”