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p53 gain‐of‐function mutations increase Cdc7‐dependent replication initiation
Author(s) -
Datta Arindam,
Ghatak Dishari,
Das Sumit,
Banerjee Taraswi,
Paul Anindita,
Butti Ramesh,
Gorain Mahadeo,
Ghuwalewala Sangeeta,
Roychowdhury Anirban,
Alam Sk Kayum,
Das Pijush,
Chatterjee Raghunath,
Dasgupta Maitrayee,
Panda Chinmay Kumar,
Kundu Gopal C,
Roychoudhury Susanta
Publication year - 2017
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201643347
Subject(s) - gain of function , biology , genetics , replication (statistics) , function (biology) , mutation , microbiology and biotechnology , gene , virology
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 CDC 7 significantly abrogates mutant p53‐driven cancer phenotypes in vitro and in vivo . Importantly, high CDC 7 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.