The Tip of an Iceberg: Replication-Associated Functions of the Tumor Suppressor p53.

Vanesa Gottifredi,Lisa Wiesmüller

doi:10.3390/cancers10080250

Abstract

The tumor suppressor p53 is a transcriptional factor broadly mutated in cancer. Most inactivating and gain of function mutations disrupt the sequence-specific DNA binding domain, which activates target genes. This is perhaps the main reason why most research has focused on the relevance of such transcriptional activity for the prevention or elimination of cancer cells. Notwithstanding, transcriptional regulation may not be the only mechanism underlying its role in tumor suppression and therapeutic responses. In the past, a direct role of p53 in DNA repair transactions that include the regulation of homologous recombination has been suggested. More recently, the localization of p53 at replication forks has been demonstrated and the effect of p53 on nascent DNA elongation has been explored. While some data sets indicate that the regulation of ongoing replication forks by p53 may be mediated by p53 targets such as MDM2 (murine double minute 2) and polymerase (POL) eta other evidences demonstrate that p53 is capable of controlling DNA replication by directly interacting with the replisome and altering its composition. In addition to discussing such findings, this review will also analyze the impact that p53-mediated control of ongoing DNA replication has on treatment responses and tumor suppressor abilities of this important anti-oncogene.

Highlights

Division of Gynecological Oncology, Department of Obstetrics and Gynecology of the University of Ulm, Prittwitzstrasse 43, 89075 Ulm, Germany
While some data sets indicate that the regulation of ongoing replication forks by p53 may be mediated by p53 targets such as MDM2 and polymerase (POL) eta other evidences demonstrate that p53 is capable of controlling
An elaborated analysis involving the use of SIRF technology [42] revealed that p53 promotes the recruitment to stalled forks of the MLL3 chromatin remodeler and the MRE11 nuclease

Summary

The Control of Nascent DNA Elongation by p53

While some manuscripts have lately explored a role of p53 in DNA replication, the use of the iPOND (isolation of proteins on nascent DNA technology) has recently demonstrated that p53 is yet another factor escorting ongoing replication forks [22]. DNA spreading assays (20 min CldU + 20 min IdU) demonstrated both p53 and POLι were required to constrain replication elongation both in unperturbed conditions and after treatment of cells with MMC. Such observation is in line with the proposal of a direct role of p53 at replication forks [36] While this manuscript utilizes the DNA spreading technology, the approach was slightly different and difficult to compare with the two previous manuscripts. An elaborated analysis involving the use of SIRF (in situ interactions at replication forks using PLA) technology [42] revealed that p53 promotes the recruitment to stalled forks of the MLL3 chromatin remodeler and the MRE11 nuclease (which is in line with a previous study [36]) Such an alteration in replisome composition prevented the localization of RAD52 and POLθ to such EdU positive sites on the DNA [22]. As suggested by Hampp et al and Roy et al, p53 likely promotes remodeling at stalled forks facilitating replication continuity driven by nonmutagenic pathways [22,36]

Biological Relevance of the Participation of p53 in the Replisome

MDM2 Is a p53 Target That Promotes Nascent DNA Elongation

POLη Is a Target of p53 That Promotes Nascent DNA Elongation

Biological

Concluding Remarks