Kyle Miller obtained his Ph.D. from University College London, working in the lab of Julie Cooper at the London Research Institute. His Ph.D. work focused on studying telomeres and their roles in replication and genome maintenance in fission yeast (2004). He then was a postdoctoral fellow at the University of California San Francisco focusing on chromatin and genome stability in budding yeast in the lab of Dr. David Tocyzski. He next completed another postdoctoral training in the lab of Prof. Stephen Jackson at the Gurdon Institute, University of Cambridge, England. This work focused on understanding the role of histone modifications and chromatin modifying enzymes in DNA double-strand break repair. In 2011, he joined the faculty of The University of Texas at Austin. He is also a member of the Livestrong Cancer Institute (Dell Medical School, UT Austin) and an adjunct member of the Dan Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Currently, his research aims to understand genome maintenance and the DNA damage response in the context of chromatin, cancer and anticancer therapies. His lab employs genetics, genomics, cell biology and molecular biology in both mouse and human tissue culture systems to gain insights into these areas of research. His lab applies these multifaceted and diverse approaches to these areas of research in hopes of defining the relationship between chromatin and DNA damage responses, as well as gaining insights into the mechanisms of cancer therapeutic drugs that act at the chromatin and DNA level. His work has obtained funding from the National Cancer Institute (NIH), Cancer Prevention Research Institute of Texas (CPRIT), American Cancer Society, the Keck Foundation and NASA.
DNA damage represents a formidable challenge to genome maintenance. To protect our genetic material, our cells have evolved multifaceted systems, collectively termed the DNA damage response (DDR), to detect and repair damaged DNA. It is clear that the true in vivo substrate of the DDR is not "naked" DNA but rather DNA assembled into chromatin. The structure and function of chromatin are regulated by histone modifications and chromatin modifying enzymes, which can markedly influence the DDR. Therefore, determining the interplay between the DDR and chromatin is fundamental for elucidating how cells maintain both epigenetic and genome integrity. The relevance of this research is highlighted by recent studies showing that mutations in many genes involved in the DDR and chromatin lead to cancer predisposition in humans. Therefore, we believe that deciphering the function of these pathways, both in normal and cancer cells, will contribute to the development of novel cancer therapies. Our research utilizes genetics, genomics, cell biology and molecular biology in both mouse and human tissue culture systems to gain insights into these areas of research. The lab also has interests in understanding anti-cancer drug mechanisms that function through DNA damage and chromatin. Many current drugs used in the clinic for cancer treatments act through DNA damage induction and pathways that regulate chromatin represent new targets for drug discovery. To explore this area of research, we employ a combination of chemical and molecular biology techniques to determine the in vivo interactions of small molecules (drugs) both at the cellular and molecular level. Taken together, the lab aims to engage in an active research program that applies a multifaceted and diverse approach to these questions in hopes of defining the relationship between chromatin and the DDR, as well as gaining insights into the mechanisms of cancer therapeutic drugs that act at the chromatin and DNA level.
Fields of Interest
- Cell and Developmental Biology
- Molecular Biology and Genetics
2020 Kim, J.J.*, Lee, S.Y.*, Choi, J., Woo H.G., Xhemalce, B., Miller, K.M. PCAF-mediated histone acetylation promotes replication fork degradation by MRE11 and EXO1 in BRCA-deficient cells. Molecular Cell 2020; Sep 20:S1097-2765(20)30581-5
2019 Kim, J.J.*, Lee, S.Y.*, Gong, F., Battenhouse, A.M., Boutz, D.R., Bashyal, A., Refvik, S.T., Chiang, C.M., Xhemalce, B., Paull, T.T., Brodbelt, J.S., Marcotte, E.M., Miller, K.M. Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity. Genes & Development. 33 (23-24):1751-74.
2019 Xia J*, Chiu L-Y*, Nehring RB, Bravo Núñez MA, Mei Q, Perez M, Zhai Y, Fitzgerald DM, Pribis JP, Wang Y, Wang Y, Hu CW, Powell RT, LaBonte SA, Jalali A, Matadamas Guzmán ML, Lentzsch AM, Szafran AT, Joshi MC, Richters M, Gibson JL, Frisch RL, Hastings PJ, Bates D,Queitsch C, Hilsenbeck S, Coarfa C, Hu JC, Siegele DA, Scott KL, Liang H, Mancini MA, Herman C1, Miller KM1and Rosenberg SM1. Bacteria-to-human protein networks reveal origins of endogenous DNA damage. Cell. Jan 10;176(1-2):127-143, (*Co-first author, 1co-corresponding authors).
2018 Leung J.W.C., Emery L.E., Miller K.M.CRISPR/Cas9 Gene Editing of Human Histone H2A Variant H2AX and MacroH2A. In: Orsi G., Almouzni G. (eds) Histone Variants. Methods in Molecular Biology. 1832:255-269.
2018 Vilas, C.K., Emery, L.E., Denchi E. L.1and Miller K.M.1Caught with one’s zinc fingers in the genome integrity cookie jar. Trends in Genetics. 34(4):313-325. (1co-corresponding authors).
2017 Gong, F., Clouaire, T., Aguirrebengoa, M., Legube, G., and Miller, K.M. Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. Journal of Cell Biology. June 1st AOP
2017 Zacharioudakis, E.*, Agarwal, P.*, Bartoli, A., Abell, N., Xhemalce, B., Miller, K.M.1, and Rodriguez, R.1 Pharmacological alterations of chromatin reprograms genome targeting with cisplatin. Angewandte Chemie. (*Co-first author, 1co-corresponding authors).
2017 Leung, J.W., Makharashvili, N., Agarwal, P., Pourpre, R., Cammarata, M.B., Cannon, J.R., Sherker, A., Durocher, D., Brodbelt, J.S., Paull, T.T., & Miller, K.M. ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair. Genes & Development. Feb 1;31(3):260-274
2016 Gong, F., Chiu, L.Y., and Miller, K.M. Acetylation reader proteins: linking acetylation signaling to genome maintenance and cancer. PLoS Genetics. Sep 15;12(9):e1006272. (Invited review.)
2016 Gruosso, T., Mieulet, V., Cardon, M., Bourachot, B., Kieffer, Y., Devun, F., Dubois, T., Dutreix, M., Vincent-Salomon, A., Miller, K.M., and Mechta-Grigoriou, F. Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients. EMBO Mol. Medicine, Mar 22; Epub ahead of print.
2015 Chen, W., Ebelt, N.D., Stracker, T.H., Xhemalce, B., Van Den Berg, C.L., and Miller, K.M. ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion. Elife, Jun 1;4.
2015 Gong F*, Chiu L*, Cox B, Aymard F., Clouaire T, Leung JW, Cammarata M, Perez M, Agarwal P, Brodbelt JS, Legube G & Miller KM. Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination. Genes & Development, 29:197-211. (*authors contributed equally).
2015 Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E & Sfeir A. Mammalian Polymerase Theta Promotes Alternative-NHEJ and Suppresses Recombination. Nature, 12;518(7538):254-7. (Highlighted in Nature News & Views by Cho and Greenberg and Nature Reviews Cancer by Villanueva).
2014 Rodriguez RR & Miller KM. Unraveling the genomic targets of small molecules using high-throughput sequencing. Nature Reviews Genetics, Dec;15(12):783-96. (Invited review article)
2014 Leung JW*, Agarwal P*,Canny MD, Gong F, Robison AD, Finkelstein IJ, Durocher D & Miller KM. Nucleosome Acidic Patch Promotes RNF168- and RING1B/BMI1-Dependent H2AX and H2A Ubiquitination and DNA Damage Signaling. PLOS Genetics, 10(3): e1004178. (*authors contributed equally).
2014 Aymard F, Bugler B, Schmidt CK, Guillou E, Caron P, Briois S, Iacovoni JS, Daburon V, Miller KM, Jackson SP, Legube G. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks. Nature Structural & Molecular Biology (2014), 21:366-74.
2013 Shee, C., Cox, B., Gu, F., Luengas, E., Joshi, M., Chiu, L., Magnan, D., Halliday, J., Frisch, R., Gibson, J., Nehring, R., Do, H., Hernandez, M., Li, L., Herman, C., Hanstings, P.J., Bates, D., Harris, R1., Miller, K.M. 1, & Rosenberg, S. 1 Engineered proteins detect spontaneous DNA breakage in human and bacterial cells. eLife, 2:e01222. (1co-corresponding authors)
2012 Rodriguez R*, Miller KM*, Forment JV, Bradshaw CR, Nikan M, Xhemalce B, Balasubramanian S1 and Jackson SP1, Small molecule inducer of double strand breaks identifies druggable alternatively-structured DNA sites. Nature Chemical Biology 8: 301-310
2010 Devanshi J, Hebden AK, Nakamura TM, Miller KM and Cooper JP, HAATI survivors replace canonical telomeres with blocks of generic heterochromatin, Nature 467(7312): 223-7
2010 Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S and Jackson SP, Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA non-homologous end-joining, Nature Structural & Molecular Biology . Aug 29th; 17: 1144
2009 Tjeertes JV*, Miller KM*1 and Jackson SP1, Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells , EMBO J 28(13): 1878-89
2009 Galanty Y, Belotserkovskaya R, Coates J, Polo SE, Miller KM and Jackson SP, SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks in mammalian cells, Nature Dec 17;462 (7275): 857-8
2007 Collins SR, Miller KM, Maas NL, Roguev A, Fillingham J, Chu CS, Schuldiner M, Gebbia M, Recht J, Shales M, Ding H, Xu H, Han J, Ingvarsdottir K, Cheng B, Andrews B, Boone C, Berger SL, Hieter P, Zhang Z, Brown GW, Ingles CJ, Emili A, Allis CD, Toczyski DP, Weissman JS, Greenblatt JF and Krogan NJ, . Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map , Nature. Apr 12; 446 (7137): 806-10
2006 Miller KM*, Rog O* and Cooper JP, The telomere protein Taz1 is required for conventional DNA replication through telomeres, Nature Apr 6;440 (7085): 824-8
2003 Miller KM and Cooper JP, The Telomere Protein Taz1 is Required to Prevent and Repair Genomic DNA Breaks, Mol Cell Vol. 11: 303-313
- Fellow of the Lorene Morrow Kelley Professorship
- Rom Rhome Travel Award
- William H. Tonn Professional Assistance Fund Fellow
- Research Scholar of the American Cancer Society
- W.M. Keck Foundation Award (Co-PI)
- Institute for Cellular and Molecular Biology Fellowship
- CPRIT Scholar