Cancer Biology: the Dark Side Of

RESEARCH HIGHLIGHTS

Nature Reviews Molecular Cell Biology | Published online 6 July 2016; doi:10.1038/nrm.2016.90

CANCER BIOLOGY The dark side of p21

The cyclin-dependent kinase inhib- proliferative and other effects of p21 decreased replication fork reversal itor p21 is a major effector of the expression in a p53-null background, (maintenance) and accumulated prolonged p21 tumour suppressor p53. It mediates an inducible p21 module was stretches of single-stranded DNA expression in cell cycle arrest in the G1 phase and introduced into two p53-null cell at replication forks. DNA damage cell senescence in response to several types — the osteosarcoma cell line accumulation following replication p53-deficient stimuli, including oncogene-induced Saos2 and precancerous Li–Fraumeni stress was dependent on the activity cells can proliferation. However, p21 can be syndrome-derived fibroblasts. of the structure-specific resolvase deregulate activated independently of p53 and Following p21 induction, the growth complex MUS81–EME1, and damage DNA has cancer-promoting properties, rate of the cells was reduced and repair was dependent on RAD52, such as supporting tumour growth they accumulated in G1, despite an which is involved in the error-prone replication in mice, the mechanisms of which increase in the protein levels of DNA microhomology-mediated repair. are unclear. Galanos et al. now report replication licensing factors, such Sustained p53-independent that prolonged p21 expression in as CDT1 and CDC6 (cell division p21 expression in the Saos2 and p53-deficient cells leads to deregu control protein 6 homologue). Li–Fraumeni syndrome cells trig- lation of DNA replication and CDT1, CDC6 and p21 are all gered their senescence in a manner genomic instability. ubiquitylated by the E3-ubiquitin that was dependent on CDT1 and When examining various ligase complex CRL4–CDT2. Unlike CDC6. However, 10 days after p21 p53-deficient human carcinomas wild-type p21, the expression of a induction, subpopulations of pro and precancerous lesions, the p21 mutant that cannot be targeted liferating cells progressively emerged authors found atypical cells that for degradation by CRL4–CDT2 did that expressed p21, Ki67, and CDC6 expressed both p21 and the pro not lead to higher levels of CDT1 and and/or CDT1. In these ‘escaped cells’, liferation marker Ki67. To study the CDC6, and shutting-off wild-type DNA damage was reduced through p21 expression led to ubiquitylation- the activity of MUS81–EME1– dependent decrease of CDT1 levels. RAD52 and this was accompanied by By contrast, induction of p21 expres- the appearance of micronuclei, which sion in wild-type p53 cells resulted indicates that the repair was error- in considerable apoptosis and a prone. Consequently, the escaped decrease in CDT1 and CDC6 levels. cells exhibited various chromosomal These results indicate that, in the aberrations and even chromosome absence of p53, high p21 levels may shattering and reconstitution. saturate CRL4–CDT2 and lead to Furthermore, the cells acquired the accumulation of its other targets, enhanced anchorage-independent including CDT1 and CDC6. growth and invasiveness in vitro and Inappropriate expression higher tolerance to treatment with of replication licensing factors genotoxic anticancer drugs. results in unscheduled replication In summary, prolonged p21 (re-replication), replication stress expression in p53-deficient cells and DNA damage. Expression of can deregulate DNA replication and p21, but not of the CRL4–CDT2- could have prognostic and therapeutic resistant p21 mutant, led to the implications for cancer. accumulation of DNA damage and Eytan Zlotorynski cells with doubled DNA content, ORIGINAL ARTICLE Galanos, P. et al. Chronic which is indicative of re-replication; p53-independent p21 expression causes genomic depletion of CDT1 and CDC6 instability by deregulating replication licensing. Nat. Cell Biol. http://dx.doi.org/10.1038/ncb3378 abolished these effects. Inspection (2016) of replication intermediates by FURTHER READING Fragkos, M. et al. DNA electron microscopy revealed that, replication origin activation in space and time. Stocksnapper/Alamy Nat. Rev. Mol. Cell Biol. 16, 360–374 (2015) upon p21 expression, Saos2 cells