Professor, Biology
Sagalowsky Professor of Biology
Director, GCDB Graduate Program
Core Faculty, Biochemistry Graduate Program
Currently recruiting graduate students: Yes
Currently recruiting graduate students: Yes
Biology Bldg. 327
Hundley Lab website
RNA plays a central role in the expression of genes in all organisms. Understanding how the cell decides which RNAs to express at a given time is a fundamental question in biology. Work in the Hundley lab is centered on a conserved family of proteins, called ADARs, which can affect gene expression through both binding RNA and modifying specific nucleotides (referred to as RNA editing). Both RNA editing and RNA binding are essential functions of human ADARs and dysregulated in over 35 human diseases.
Deciphering the fundamentals of RNA recognition by ADARs: As ADARs can effectively rewrite the genetic code, the recognition of target RNAs must be tightly controlled. Work in the Hundley lab is focused on understanding the in vivo rules that govern ADAR interactions with target RNAs. We use a number of biochemical and genomic techniques to profile both RNAs bound by ADARs as well as those edited by ADARs. Recently, we have also become intrigued by how ADAR recognition of target RNAs can be influenced by changes in the environment to dynamically regulate gene expression and RNA editing.
Regulation of RNA editing: In many diseases and across human tissues during normal development, ADAR expression does not directly correlate with the extent of editing at individual adenosines. Furthermore, spatiotemporal editing patterns vary for individual genes, suggesting that specific factors bind target mRNAs to regulate editing in vivo. To date, we have demonstrated that the editing-deficient members of the ADAR family can influence substrate recognition and editing in both the model organism C. elegans and human glioblastoma (brain cancer) cell lines. Our ongoing work is focused on identifying additional proteins that regulate editing (particularly in a tissue-specific manner) as well as understanding how subcellular localization and other cellular processes (ex. transcription, RNA modification by other enzymes, etc.) alter ADAR function.
Connecting tissue-specific mechanisms of gene regulation to organismal physiology: ADARs play important roles in diversifying the transcriptome. We take advantage of the genetic amenability of the model organism C. elegans to not only monitor ADARs effects on different tissues, but also dissect the molecular mechanisms of how ADARs edit and/or bind RNA uniquely in specific tissues and connect that information to impacts on organismal behavior and/or survival. We have done extensive work on how ADARs bind and edit transcripts in the nervous system and revealed mechanisms that regulate sensing of chemicals and survival to hypoxia (low oxygen). We are also actively exploring how ADARs sense and respond to pathogen infection and impacts of ADARs on other tissues, including the germline.
Oncogenic roles of ADARs: Defects in editing are known to result in misexpression of both tumor suppressors and oncogenes in many cancer types. Our work has focused on the regulation of editing in glioblastoma, a malignant form of brain cancer. We have shown that ADAR3, a deaminase-deficient member of the ADAR family, is a key regulator of RNA editing and expression of ADAR3 is elevated in tissue isolated from glioblastoma patients. Most recently, we have demonstrated that ADAR3 expression results in a gene expression program that provides glioblastoma cells with resistance to irradiation and temozolomide, two standard-of-care therapies. Going forward, we want to understand how ADAR3 expression and activity are regulated and the molecular targets of ADAR3 in glioblastoma.
Research Areas
Chromatin, Chromosomes, and Genome Integrity
Developmental Mechanisms and Regulation in Eukaryotic Systems
Genomics and Bioinformatics
Eliad B, Schneider N, Ben-Naim Zgayer O, Amichan Y, Glaser F, Erdmann EA, Rajendren S, Hundley HA and Lamm AT and (2024) ADBP-1 regulates ADR-2 nuclear localization to control editing substrate selection. NAR, in press.
Dhakal A, Salim C, Skelly M, Amichan Y, Lamm AT and Hundley HA (2024) ADARs regulate cuticle collagen expression and promote organismal survival to pathogen infection. BMC Biology, 2024 Feb 16;22(1):37
Mahapatra A, Dhakal A, Noguchi A, Vadlamani P and Hundley HA (2023) ADAR-mediated regulation of PQM-1 expression in neurons impacts gene expression throughout C. elegans and regulates survival from hypoxia. PLOS Biology, 2023 Sep 25;21(9):e3002150.
Raghava Kurup R, Oakes EK, Vadlamani P, Nwosu O, Danthi P and Hundley HA (2022) ADAR3 activates NF-kB signaling and promotes glioblastoma cell resistance to temozolomide, Scientific Reports, 2022 Aug 3;12(1):13362. doi: 10.1038/s41598-022-17559-4.
Raghava Kurup R, Oakes EK, Manning AC, Mukherjee P, Vadlamani P and Hundley HA (2022) RNA binding by ADAR3 inhibits adenosine-to-inosine editing and promotes expression of the immune response protein MAVS, JBC, 2022 Jul 15;102267. doi: 10.1016/j.jbc.2022.102267.
Erdmann EA, Abraham O and Hundley HA (2022) Caenorhabditis elegans expressing a Vitellogenin: GFP fusion protein show reduced embryo content and brood size, Micropublication Biology, 2022 Mar 1; 202210.17912/micropub.biology.000532
Mukherjee P*, Raghava Kurup R* and Hundley HA (2021) RNA immunoprecipitation to find targets of RNA modification enzymes, Methods in Enzymology: RNA Modification Enzymes, 2021;658:137-160.
Erdmann EA, Mahapatra A, Mukherjee P, Yang B and Hundley HA (2021) To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis. Critical Reviews in Biochemistry and Molecular Biology, 2021 Feb; 56(1):54-87.
Rajendren S, Dhakal A, Vadlamani P, Townsend J, Deffit SN and Hundley HA (2021) Profiling neural editomes reveals a molecular mechanism to regulate RNA editing during development. Genome Research, 2021 Jan;31(1):27-39.
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