Datta A, A. and Ghatak D, D. and Das S2, , S. and Banerjee T, T and Paul A4, , A and Butti R2,, R and Gorain M2, , M and Ghuwalewala S1, S and Roychowdhury A, A and Alam SK1,, S.K. and Das P1, , P. and Chatterjee R6,, R. and Dasgupta M4,, M. and Panda CK5,, C.K. and Kundu GC2, , G.C. and Roychoudhury S7,8., S. (2017) p53 gain-of-function mutations increase Cdc7-dependent replication initiation. EMBO Report.

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Abstract

Cancer-associated p53 missense mutants confer gain of function (GOF) and promote tumorigenesis by regulating crucial signaling pathways. However, the role of GOF mutant p53 in regulating DNA replication, a commonly altered pathway in cancer, is less explored. Here, we show that enhanced Cdc7-dependent replication initiation enables mutant p53 to confer oncogenic phenotypes. We demonstrate that mutant p53 cooperates with the oncogenic transcription factor Myb in vivo and transactivates Cdc7 in cancer cells. Moreover, mutant p53 cells exhibit enhanced levels of Dbf4, promoting the activity of Cdc7/Dbf4 complex. Chromatin enrichment of replication initiation factors and subsequent increase in origin firing confirm increased Cdc7-dependent replication initiation in mutant p53 cells. Further, knockdown of CDC7 significantly abrogates mutant p53-driven cancer phenotypes in vitro and in vivo Importantly, high CDC7 expression significantly correlates with p53 mutational status and predicts poor clinical outcome in lung adenocarcinoma patients. Collectively, this study highlights a novel functional interaction between mutant p53 and the DNA replication pathway in cancer cells. We propose that increased Cdc7-dependent replication initiation is a hallmark of p53 gain-of-function mutations.

Item Type:	Article
Subjects:	Cell Biology
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	05 Dec 2017 06:13
Last Modified:	05 Dec 2017 06:13
URI:	http://nccs.sciencecentral.in/id/eprint/456

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