p53 gain-of-function mutations increase Cdc7-dependent replication initiation.

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.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Datta A,Ghatak D,Das S,Banerjee T,Paul A,Butti R,Gorain M,Ghuwalewala S,Roychowdhury A,Alam SK,Das P,Chatterjee R,Dasgupta M,Panda CK,Kundu GC,Roychoudhury S

doi

10.15252/embr.201643347

subject

Has Abstract

pub_date

2017-11-01 00:00:00

pages

2030-2050

issue

11

eissn

1469-221X

issn

1469-3178

pii

embr.201643347

journal_volume

18

pub_type

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