Abstract:Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomeriza… Show more
“…p53 has well-described roles in ensuring normal segregation of chromosomes at mitosis, being involved in normal centrosome clustering 40 and in the operation of mitotic checkpoint controls 48 . Conversely, mutant oncogenic p53 function is permissive of abnormal mitotic events, and permits passage through mitotic checkpoints that would otherwise induce apoptotic cell death of abnormal cells, causing chromosomal changes 49 , 50 . Fig.…”
Cell-in-cell (CIC) structures are commonly seen in tumours. Their biological significance remains unclear, although they have been associated with more aggressive tumours. Here we report that mutant p53 promotes CIC via live cell engulfment. Engulfed cells physically interfere in cell divisions of host cells and for cells without p53 this leads to host cell death. In contrast, mutant p53 host cells survive, display aberrant divisions, multinucleation and tripolar mitoses. In xenograft studies, CIC-rich p53 mutant/null co-cultures show enhanced tumour growth. Furthermore, our results show that CIC is common within lung adenocarcinomas, is an independent predictor of poor outcome and disease recurrence, is associated with mutant p53 expression and correlated to measures of heterogeneity and genomic instability. These findings suggest that pro-tumorigenic entotic engulfment activity is associated with mutant p53 expression, and the two combined are a key factor in genomic instability.
“…p53 has well-described roles in ensuring normal segregation of chromosomes at mitosis, being involved in normal centrosome clustering 40 and in the operation of mitotic checkpoint controls 48 . Conversely, mutant oncogenic p53 function is permissive of abnormal mitotic events, and permits passage through mitotic checkpoints that would otherwise induce apoptotic cell death of abnormal cells, causing chromosomal changes 49 , 50 . Fig.…”
Cell-in-cell (CIC) structures are commonly seen in tumours. Their biological significance remains unclear, although they have been associated with more aggressive tumours. Here we report that mutant p53 promotes CIC via live cell engulfment. Engulfed cells physically interfere in cell divisions of host cells and for cells without p53 this leads to host cell death. In contrast, mutant p53 host cells survive, display aberrant divisions, multinucleation and tripolar mitoses. In xenograft studies, CIC-rich p53 mutant/null co-cultures show enhanced tumour growth. Furthermore, our results show that CIC is common within lung adenocarcinomas, is an independent predictor of poor outcome and disease recurrence, is associated with mutant p53 expression and correlated to measures of heterogeneity and genomic instability. These findings suggest that pro-tumorigenic entotic engulfment activity is associated with mutant p53 expression, and the two combined are a key factor in genomic instability.
“…The same goes for the impact of mutant p53 on interactions with RAD52, POLθ and other translesion polymerases. In the presence of exogenous replication stress, the hotspot mutants R175H and R273H have also been shown to induce TopBP1 oligomerization, which attenuates its ability to activate ATR-mediated checkpoints that control origin firing and downstream phosphorylation of CHK1 [36].…”
It has been four decades since the discovery of p53, the designated ‘Guardian of the Genome’. P53 is primarily known as a master transcription factor and critical tumor suppressor, with countless studies detailing the mechanisms by which it regulates a host of gene targets and their consequent signaling pathways. However, transcription-independent functions of p53 also strongly define its tumor-suppressive capabilities and recent findings shed light on the molecular mechanisms hinted at by earlier efforts. This review highlights the transcription-independent mechanisms by which p53 influences the cellular response to genomic instability (in the form of replication stress, centrosome homeostasis, and transposition) and cell death. We also pinpoint areas for further investigation in order to better understand the context dependency of p53 transcription-independent functions and how these are perturbed when TP53 is mutated in human cancer.
“…This binding is required for Cdc45 loading on chromatin and for replication initiation, although the mechanism by which these proteins identify prospective replication initiation sites is not known. The binding of TopBP1 to CDKphosphorylated Treslin is also necessary for activation of the ATR/pChk1 DNA damage response (15,24). We therefore tested whether the downregulation of the chromatin binding of Treslin by DUE-B depletion would also inhibit the UV-induced DNA damage response.…”
A key step in the initiation of eukaryotic DNA replication is the binding of the activator protein Cdc45 to promote MCM helicase unwinding of the origin template. We show here that the c-myc origin DNA unwinding element binding protein, DUE-B, interacts in HeLa cells with the replication initiation protein Treslin to allow Cdc45 loading onto chromatin. The chromatin loading of DUE-B and Treslin are mutually dependent, and the DUE-B-Treslin interaction is cell cycle regulated to peak as cells exit G1 phase prior to the initiation of replication. The conserved C-terminal domain of DUE-B is required for its binding to TopBP1, Treslin, Cdc45 and the MCM2-7 complex, as well as for the efficient loading of Treslin, Cdc45 and TopBP1 on chromatin. These results suggest that DUE-B acts to identify origins by MCM binding, and serves as a node for replication protein recruitment and Cdc45 transfer to the pre-replication complex.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
