Member Biography


Edward Motea

Edward Motea, Ph.D.

980 West Walnut Street
R3-C551
INDIANAPOLIS, IN 46202
Phone: (317) 278-5249
Fax: (317) 274-8046

Research Program Membership

Associate member:

Assistant Professor
Department of Biochemistry and Molecular Biology
IU School of Medicine

Dr. Motea's research interests include:

The goal of my research program is to discover and understand how cancer cells promote and/or avert critical mechanisms of survival/growth at the basic molecular level using biochemistry, molecular biology, enzymology and chemical biology approaches. Specifically, my research will focus on (1) discovering and characterizing novel factors in DNA damage and repair; (2) understanding the unannotated role of co-transcriptional DNA:RNA hybrids or R-loops in genomic instability; and (3) elucidating the mechanistic basis for the replication bypass of damaged DNA by DNA polymerases. Overall, the mechanistic insights gained from my research program should ultimately lead to the identification of novel chemical agents, biomarkers, druggable targets and innovative strategies to selectively stop malignant cells while sparing healthy cells for personalized medicine in the clinic. RESEARCH PROGRAM 1: RPRD1B (also known as Kub5-Hera (K-H) or CREPT) is a factor involved in transcription and DNA repair that is commonly altered in most cancers, including breast cancer. Nevertheless, information on the protein itself or its role in cancer survival and drug resistance is extremely limited. Our lab has uncovered that RPRD1B or K-H is a novel PARP1-binding protein. K-H directly binds PARP1, poly(ADP)-ribose (PAR) moiety and modulates PARP1 activity in the presence of DNA damage using recombinant proteins, as well as total cell lysates in vitro. Loss of K-H unleashes highly error-prone PARP1 activity that potentially promotes cancer cell growth and survival following therapy. Indeed, inhibition of PARP1 activity in K-H deficient cells produced deleterious R-loop-mediated DSBs causing synthetic lethality in BRCA-proficient cells. Interestingly, inhibition of PARP1 activity alone increases persistent RNA:DNA hybrid (R loop) formation during transcription. This unannotated mechanism of action induced by PARP inhibitors (or PARP1 loss) in K-H proficient cancers warrants investigation since R-loop structures could stimulate genetic instability and lead to further malignancies when administered to the wrong patients. Thus, I hypothesize that K-H is a novel PAR-recognizing molecular scaffold that binds PARP1 (or autoPARylated-PARP1) to suppress PARP-mediated alternative non-homologous end-joining (NHEJ) and facilitate the organization/retention of classical-NHEJ repair and transcription proteins/enzymes to increase the overall efficiency and ensure proper coordination of these critical pathways. Future research interest in this area: To test other transcription termination factors such as XRN2 (5'-3'-exoribonuclease 2) and RPRD1A (regulation of nuclear pre-mRNA domain containing protein 1A, p15RS)for their functional roles in R-loop dynamics and DNA Damage Response and Repair. RESEARCH PROGRAM 2: ß-Lapachone (ß-lap) (in clinical trials as ARQ761 against NQO1+ solid cancers) and IB-DNQ are unique chemical agents that undergo a futile NQO1-mediated redox cycle that generates massive reactive oxygen species (ROS, e.g., superoxide radical, H2O2, etc.) specifically in cancer cells that overexpress NQO1 (frequency ranges from 60-90% in most cancers; normal tissues overexpress Catalase that quenches ROS). Recently, we found that PARP inhibitors can selectively potentiate the effects of sub-lethal ß-lap doses by generating massive amount of DNA damage that are not repaired due to the inhibition of the main sensor, signaling, and repair protein, PARP1 (published in Cancer Cell). We have also shown that low dose IR can synergize with sub-lethal doses of ß-lap by depleting the energy sources (ATP and NAD+) needed to carry out critical DNA repair pathways. During the course of these studies, I became increasingly intrigued in the potential synergy between FDA-approved c-Met inhibitors (e.g., crizotinib) and NQO1 bioactivatable drugs. c-Met is a tyrosine-protein kinase that phosphorylates PARP1 for activity in the presence of ROS. Thus, I proposed that inhibition of c-Met would compromise PARP activity that is critical for the repair of oxidatively damaged DNA caused by sub-lethal doses of ß-lap (or IB-DNQ) leading to synergistic cell death in NQO1-expressing pancreatic, lung, or breast cancers. Indeed, my preliminary studies support this hypothesis and I want to further investigate the mechanism of lethality and cell death with this drug combination in vitro and in vivo. Future research interest in this area: (1) To test crosslinking, alkylating prodrugs converted by ROS in a tumor-specific manner via NQO1, which is overexpressed in most cancers. (2) In my graduate training, I developed a series of biochemical tools/agents that are selectively incorporated opposite abasic sites in the DNA formed by the cleavage of damaged nitrogenous bases (e.g., 8-oxoguanine, which is an oxidatively damaged guanine base) by specific glycosylases. Upon selective incorporation opposite abasic sites, these non-natural nucleotides terminate DNA replication leading to replication fork collapse and cell death. Since NQO1-bioactivatable drugs produce ROS that oxidatively damage DNA bases to eventually form abasic sites, I propose that selective incorporation of non-natural nucleotides opposite these lesions will lead to cell death at sub-lethal doses of each drug. By “click” chemistry, I can quantify the extent of nucleotide incorporation needed to achieve cell death. I am also interested in further investigating the mechanism of lethality and cell death with this drug combination in vitro and in vivo.

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More Publications »

Post-doctoral Fellowship - UT Southwestern Medical Center, Dallas, TX 10/2017

Ph.D. - Case Western Reserve University, Cleveland, OH 01/2012