p53 Activity Results in DNA Replication Fork Processivity

Abstract

p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This is observed in tumor-derived U2OS cells but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion and in freshly isolated thymocytes from mice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supports DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53's tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity; i.e., the prevention of DNA damage during replication.

Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes

“…The tumor suppressor p53 determines the fate of HDACitreated cells (Mrakovcic et al 2019) and is relevant for DNA replication and HR (Gottifredi and Wiesmüller 2018;Klusmann et al 2016). As we see replication stress/DNA damage in HDACi-treated cells (Fig.…”

“…Since wild-type p53 is a tumor suppressor (Gottifredi and Wiesmüller 2018;Klusmann et al 2016), its reduction by HDACi raises concerns that such drugs promote chemoresistance. Furthermore, HDACi-induced alterations in EMT factors (Kiweler et al 2018) may promote the mesenchymal phenotype that is linked to chemoresistance (Fischer et al 2015;Zheng et al 2015).…”

Perturbations in the Replication Program Contribute to Genomic Instability in Cancer

“…Another potential target is gain of function p53 (GOF p53), a mutant p53 with oncogenic qualities. GOF p53 increases expression of necessary replication proteins and has recently been shown to stabilize replication forks preventing unmanageable levels of stress [108]. …”

DNA replication stress: oncogenes in the spotlight

“…It has been shown that MDM2 overexpression inhibits origin firing through activation of the intra S-phase checkpoint, causing unscheduled DNA replication (Frum et al, 2014). Conversely, it has also been shown that p53 activation and subsequent MDM2 upregulation both enhance replication fork progression and increase replication fork processivity (Klusmann et al, 2016). Although these findings appear conflicting, it is tempting to speculate that disruption of the p53/MDM2 axis in human cancers, either by TP53 mutation or MDM2 overexpression, may interfere with origin firing and replication fork stability.…”