Peer-Reviewed Journal Details
Mandatory Fields
FitzGerald, J,Murillo, LS,O'Brien, G,O'Connell, E,O'Connor, A,Wu, K,Wang, GN,Rainey, MD,Natoni, A,Healy, S,O'Dwyer, M,Santocanale, C
2014
June
Plos One
A High Through-Put Screen for Small Molecules Modulating MCM2 Phosphorylation Identifies Ryuvidine as an Inducer of the DNA Damage Response
Published
WOS: 5 ()
Optional Fields
CDC7 KINASE INHIBITORS CELL-CYCLE REGULATION DOUBLE-STRAND BREAKS S-PHASE TOPOISOMERASE-II CANCER-THERAPY IONIZING-RADIATION REPLICATION STRESS ANTITUMOR-ACTIVITY PROTEIN
9
DNA replication is an essential process for cell division and as such it is a process that is directly targeted by several anticancer drugs. CDC7 plays an essential role in the activation of replication origins and has recently been proposed as a novel target for drug discovery. The MCM DNA helicase complex (MCM2-7) is a key target of the CDC7 kinase, and MCM phosphorylation status at specific sites is a reliable biomarker of CDC7 cellular activity. In this work we describe a cell-based assay that utilizes the "In Cell Western Technique'' (ICW) to identify compounds that affect cellular CDC7 activity. By screening a library of approved drugs and kinase inhibitors we found several compounds that can affect CDC7-dependent phosphorylation of MCM2 in HeLa cells. Among these, Mitoxantrone, a topoisomerase inhibitor, and Ryuvidine, previously described as a CDK4 inhibitor, cause a reduction in phosphorylated MCM2 levels and a sudden blockade of DNA synthesis that is accompanied by an ATM-dependent checkpoint response. This study sheds light on the previously observed cytotoxity of Ryuvidine, strongly suggesting that it is related to its effect of causing DNA damage.
10.1371/journal.pone.0098891
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