Motea Lab

The research laboratory of Edward A. Motea, PhD is studying the molecular basis of carcinogenesis and genomic instability induced by endogenous and exogenous genotoxic agents, translesion DNA synthesis, persistent R-loops (RNA:DNA hybrid structures), and aberrant DNA damage response and repair pathways. The goal is to utilize the mechanistic insights gained from these studies to rationally develop novel therapeutic agents and innovative strategies for personalized medicine.

Focus on Drug Resistance and Aberrant Growth of Cancer Cells

A key barrier in developing precision medicine for cancers is lack of a comprehensive understanding at the molecular level of what promotes drug resistance and aberrant growth of cancer cells compared to the normal cells. For example, inhibition of a critical DNA repair factor, poly(ADP-ribose) polymerase-1 (PARP1), is a promising strategy for targeting cancers with defective DNA double-strand break (DSB) repair such as BRCA1 and BRCA2 mutation-associated breast cancers. Deficiencies in BRCA1 and BRCA2 genes can compromise homologous recombination (HR) to repair double-strand breaks created by the loss of PARP1 activity, conferring cell death by synthetic lethality.

However, the rarity of breast tumors with BRCA deficiency currently restricts the therapeutic utility of PARP inhibitor (PARPi) monotherapy and several potential molecular mechanisms of resistance for PARP1i in BRCA-deficient breast cancers have been reported. One striking paradox, though, is that approximately 24 percent of high-grade triple negative breast cancers (TNBC) without a BRCA mutation responded positively to PARP1i in Phase II clinical trials. These confounding observations clearly posit a search for suitable predictive biomarkers (i.e., markers for resistance and sensitivity), novel therapeutic targets and innovative strategies that can potentiate the DNA damaging effects of PARP1i beyond BRCA deficiencies.

Active Research

The Motea lab is investigating the mechanistic basis for synthetic lethality between loss of both PARP activity and specific transcription termination factors in BRCA-proficient cancers. Specifically, this lab team is trying to understand how cancer cells with aberrant alterations in these factors can induce formation of genotoxic R-loops (three-stranded nucleic acid structures that contain RNA:DNA hybrid and a displaced single-stranded DNA) and genomic instability at the molecular level using proteomics, genomics, bioinformatics, molecular biology, chemical biology, and pharmacological approaches.

Overall, understanding the mechanisms underlying R-loop-mediated genomic instability may provide key insights into (1) unannotated biological pathways; (2) the pathogenesis of many diseases and syndromes including cancer and neurological disorders; and (3) identification of novel targets and innovative strategies to leverage the formation, resolution, and/or processing of R-loops for precision medicine.

Current Research Funding

NIH/NCI, 1 R01 CA201489-02, Role: Co-Investigator (PI: Boothman, DA) 07/01/2016-06/30/2021

This grant focuses on the lab’s discovery that Kub5/Hera (K-H) regulates RNAPII at specific genetic promoters that include CDK1 in a subset of BRCA-proficient cancers. Loss of K-H expression compromises homologous recombination (HR) and hypersensitizes cells to PARP inhibitors. Aim 1 focuses on determining the structure/function of K-H regulation of the CTD domain of RNPII binding to specific promoter regions of CDK1. Aim 2 studies examine the therapeutic index of K-H-deficient breast cancers that are, in turn, hypersensitive to PARP inhibitors. Overlap: None.

Recent Publications

A full list of publications from the Motea Lab is available on PubMed.

Choi JS, Kim S, Motea E, Berdis A. Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents. Oncotarget. 2017 Jun 20;8(25):40804-40816. doi: 10.18632/oncotarget.17254. PubMed PMID: 28489578; PubMed Central PMCID: PMC5522278.

Yan Y, Zhou K, Xiong H, Miller JB, Motea EA, Boothman DA, Liu L, Siegwart DJ. Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors. Biomaterials. 2017 Feb;118:84-93. doi: 10.1016/j.biomaterials.2016.12.001. Epub 2016 Dec 2. PubMed PMID: 27974266.

Huang X, Motea EA, Moore ZR, Yao J, Dong Y, Chakrabarti G, Kilgore JA, Silvers MA, Patidar PL, Cholka A, et al. Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. Cancer Cell. 2016 Dec 12;30(6):940-952. doi: 10.1016/j.ccell.2016.11.006. PubMed PMID: 27960087; PubMed Central PMCID: PMC5161231.

Morales JC, Richard P, Patidar PL, Motea EA, Dang TT, Manley JL, Boothman DA. XRN2 Links Transcription Termination to DNA Damage and Replication Stress. PLoS Genet. 2016 Jul 20;12(7):e1006107. doi: 10.1371/journal.pgen.1006107. eCollection 2016 Jul. PubMed PMID: 27437695; PubMed Central PMCID: PMC4954731.

Patidar PL, Motea EA, Fattah FJ, Zhou Y, Morales JC, Xie Y, Garner HR, Boothman DA. The Kub5-Hera/RPRD1B interactome: a novel role in preserving genetic stability by regulating DNA mismatch repair. Nucleic Acids Res. 2016 Feb 29;44(4):1718-31. doi: 10.1093/nar/gkv1492. Epub 2016 Jan 26. PubMed PMID: 26819409; PubMed Central PMCID: PMC4770225.

Research Team

The Motea lab welcomes creative collaborations. There are available openings for bright and highly motivated individuals for graduate and postdoctoral positions in the lab. Please submit inquiries to eamotea@iu.edu.

Research Team

Edward A. Motea

Edward A. Motea

Assistant Professor of Biochemistry & Molecular Biology