Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

Singh, S. K.; Vaughan, Catherine; Frum, Rebecca A.; Grossman, Steven R.; Deb, Sumitra

doi:10.1172/jci87724

Cited by 36 publications

(35 citation statements)

References 70 publications

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“…Second, loss of UDG increases levels of persistent uracil and 5-FU incorporation at the replication forks that without p53 results in early S phase arrest and disintegration of the replication fork progression, as we have shown previously (24). Further support for this mechanism comes from an article published recently by Swati Palit Deb's lab (50), which has shown that lack of WT p53 increases DNA origin firing compared with p53 WT cells. In our system, more DNA origin firings would result in both more 5-FU and uracil incorporation and further disruption of these replication forks that improve the killing effect in p53-mutant or -deficient cancer cells.…”

Section: Mol Cancer Res; 16(2) February 2018supporting

confidence: 57%

Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU

Yan

Qing

Pink

et al. 2018

Molecular Cancer Research

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Thymidylate synthase (TS) inhibitors including fluoropyrimidines [e.g., 5-Fluorouracil (5-FU) and 5-Fluorodeoxyuridine (5-FdU, floxuridine)] and antifolates (e.g., pemetrexed) are widely used against solid tumors. Previously, we reported that shRNA-mediated knockdown (KD) of uracil DNA glycosylase (UDG) sensitized cancer cells to 5-FdU. Because p53 has also been shown as a critical determinant of the sensitivity to TS inhibitors, we further interrogated 5-FdU cytotoxicity after UDG depletion with regard to p53 status. By analyzing a panel of human cancer cells with known p53 status, it was determined that p53-mutated or -deficient cells are highly resistant to 5-FdU. UDG depletion resensitizes 5-FdU in p53-mutant and -deficient cells, whereas p53 wild-type (WT) cells are not affected under similar conditions. Utilizing paired HCT116 p53 WT and p53 knockout (KO) cells, it was shown that loss of p53 improves cell survival after 5-FdU, and UDG depletion only significantly sensitizes p53 KO cells. This sensitization can also be recapitulated by UDG depletion in cells with p53 KD by shRNAs. In addition, sensitization is also observed with pemetrexed in p53 KO cells, but not with 5-FU, most likely due to RNA incorporation. Importantly, in p53 WT cells, the apoptosis pathway induced by 5-FdU is activated independent of UDG status. However, in p53 KO cells, apoptosis is compromised in UDG-expressing cells, but dramatically elevated in UDG-depleted cells. Collectively, these results provide evidence that loss of UDG catalyzes significant cell death signals only in cancer cells mutant or deficient in p53. This study reveals that UDG depletion restores sensitivity to TS inhibitors and has chemotherapeutic potential in the context of mutant or deficient p53. .

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Section: Mol Cancer Res; 16(2) February 2018supporting

confidence: 57%

Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU

Yan

Qing

Pink

et al. 2018

Molecular Cancer Research

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“…Our data (Supplemental Figure 3, C-H) did not show any appreciable statistically significant acceleration of injury repair in p53-null mice. These results are consistent with our earlier report that p53-null lung cells show deregulated S phase entry but reduced ability to complete genome duplication (54). Thus, p53-depletion does not serve as a surrogate for MDM2 in repair of lung injury.…”

Section: Discussionsupporting

confidence: 93%

“…Reactions were performed in triplicate utilizing SYBR green dye, which exhibits a higher fluorescence upon binding of double-stranded DNA. The methods have been described previously (54). Reactions were performed in triplicate and repeated in 3 different sets of mice.…”

Section: Discussionmentioning

confidence: 99%

DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2

Singh¹,

Vaughan²,

Rabender³

et al. 2019

JCI Insight

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“…In a following study, it was found that mutant p53 interacts with Yes-associated protein (YAP), and together they form a complex with NF-Y, that interacts with the regulatory regions of cyclin A, cyclin B, and CDK1 genes [28]. This was further established in a genome-wide analysis showing that GOF p53 recognizes the promoters of genes encoding cyclin A (CCNA2), which is necessary for origin firing, and CHK1, which is required for preventing a collapse of replication forks, and transcriptionally activates their expression, in a cell-cycle-dependent manner, by localizing on their upstream regulatory sequences [29].…”

Section: Disruption Of Cell Cycle Controlmentioning

confidence: 90%

Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis

Stein

Rotter

Aloni-Grinstein

2019

IJMS

137

107

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The p53 protein is mutated in about 50% of human cancers. Aside from losing the tumor-suppressive functions of the wild-type form, mutant p53 proteins often acquire inherent, novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function (GOF). A growing body of evidence suggests that these pro-oncogenic functions of mutant p53 proteins are mediated by affecting the transcription of various genes, as well as by protein–protein interactions with transcription factors and other effectors. In the current review, we discuss the various GOF effects of mutant p53, and how it may serve as a central node in a network of genes and proteins, which, altogether, promote the tumorigenic process. Finally, we discuss mechanisms by which “Mother Nature” tries to abrogate the pro-oncogenic functions of mutant p53. Thus, we suggest that targeting mutant p53, via its reactivation to the wild-type form, may serve as a promising therapeutic strategy for many cancers that harbor mutant p53. Not only will this strategy abrogate mutant p53 GOF, but it will also restore WT p53 tumor-suppressive functions.

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Mutant p53 establishes targetable tumor dependency by promoting unscheduled replication

Cited by 36 publications

References 70 publications

Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU

Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU

DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2

Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis

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