p53 Maintains Genomic Stability by Preventing Interference between Transcription and Replication

Abstract

p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression.

Mdm2 selectively suppresses DNA damage arising from inhibition of topoisomerase II independent of p53

“…44 This effect was shown to be influenced by levels of TOP2A, whereas the effect in Mdm2-overexpressing SJSA-cells was not influenced by TOP2A knockdown (Supplementary Figure 10). Further, the Mdm2-dependent outcomes described herein have been shown to be p53-independent.…”

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

“…This novel observation can imply that on a cell-by-cell basis, gH2AX response to replication stress is actually dampened by the knockdown of p53, and/or that p53 facilitates fork progression under stress. A stimulatory role of p53 in stressed fork progression was found by some studies (41,42) but not others (43). Resistance to AZD1775-induced replication stress at a replication fork level likely involves a RAD18-TLS polymerase kappa-dependent tolerance pathway and a RAD51-dependent fork protection pathway (13).…”

MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

“…Our data identifies important upstream components to this pathway and raises questions about the unexpected similarities between interstrand crosslink and R-loop bypass or repair. Moreover, other fork-associated proteins implicated in mitigating transcription-replication conflicts, such as RPA, WRN, RECQL5, p53, and MCM2, are not as closely linked to the FA pathway 35,[54][55][56][57] . This may suggest that there are alternative responses to transcription-replication conflicts that depend on the nature of the R-loop itself or the context of the specific DNA sequence (i.e.…”