TY - JOUR
T1 - p53 gain-of-function mutations increase Cdc7-dependent replication initiation
AU - Datta, Arindam
AU - Ghatak, Dishari
AU - Das, Sumit
AU - Banerjee, Taraswi
AU - Paul, Anindita
AU - Butti, Ramesh
AU - Gorain, Mahadeo
AU - Ghuwalewala, Sangeeta
AU - Roychowdhury, Anirban
AU - Alam, Sk Kayum
AU - Das, Pijush
AU - Chatterjee, Raghunath
AU - Dasgupta, Maitrayee
AU - Panda, Chinmay Kumar
AU - Kundu, Gopal C.
AU - Roychoudhury, Susanta
N1 - Publisher Copyright:
© 2017 The Authors.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - Cdc7-Dbf4
KW - gain-of-function
KW - mutant p53
KW - origin firing
KW - replication
UR - http://www.scopus.com/inward/record.url?scp=85028994923&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028994923&partnerID=8YFLogxK
U2 - 10.15252/embr.201643347
DO - 10.15252/embr.201643347
M3 - Article
C2 - 28887320
AN - SCOPUS:85028994923
SN - 1469-221X
VL - 18
SP - 2030
EP - 2050
JO - EMBO Reports
JF - EMBO Reports
IS - 11
ER -