Kyle M Miller

Assistant Professor
Molecular Biosciences

Molecular mechanisms of DNA damage responses and chromatin involved in cancer and its treatments

Office Location
NMS 4.306

Postal Address
The University of Texas at Austin
Molecular Biosciences, College of Natural Sciences
2506 Speedway
Austin, TX 78712

Research Summary:

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.

Selected Publications:

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 Agarwal, P & Miller, K.M. Book Chapter: Chromatin Dynamics and DNA Repair. In: Chromatin Regulation and Dynamics Book. Elsevier

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 Agarwal, P. and Miller, K.M. The Nucleosome: Orchestrating DNA Damage Signaling and Repair within Chromatin. Biochemistry and Cell Biology, Apr 13:1-15. [Epub ahead of print].

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.

2016 Meyer, L.R., Gallardo, I.F., Zhou, Y., Gong, F., Yang, S.H., Wold, M.S., Miller, K.M., Paull T.T., and Finkelstein, I.J. Single-molecule imaging reveals the mechanism of Exo1 regulation by single-stranded DNA binding proteins. Proc Natl Acad Sci USA, Mar 1;113(9):E1170-9

2015 O'Connor, H., Lyon, N., Leung, J.W., Agarwal, P., Swaim, C., Miller, K.M., and Huibregtse, J. Ubiquitin-Activated Interaction Traps (UBAITs) identify E3 ligase binding partners. EMBO Reports,  16(12):1699-712.

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)

2013 Gong F and Miller KM. Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Aug 6, Epub ahead of print.

2013 Chen W*, Alpert A*, Leiter C, Gong F, Jackson SP1 and Miller KM1. Systematic identification of functional residues in mammalian histone H2AX. Molecular and Cellular Biology, Jan; 33 (1):111-26. (*authors contributed equally, 1co-corresponding authors).

2012 Miller KM* and Jackson SP*, Histone marks: repairing DNA breaks within the context of chromatin, Biochemical Society Review 40(2): 370-6

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 Rog O, Miller KM, Ferreira MG, and Cooper JP, Sumoylation of RecQ helicase controls the fate of dysfunctional telomeres , Mol Cell Mar 13;33(5): 559-669

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

2006 Maas NL*, Miller KM*, DeFazio LG and Toczyski DP, Cell cycle and checkpoint regulation of histone H3 K56 acetylation by Hst3/4, Mol Cell Jul 7;23 (1): 109-19

2005 Miller KM, Ferreira MG and Cooper JP, Taz1, Rap1 and Rif1 act both inter-dependently and independently to maintain telomeres, EMBO J Sep 7;24(17): 3128-35

2004 Ferreira MG*, Miller KM* and Cooper JP, . Indecent exposure. When telomeres become uncapped, Mol Cell Vol. 13 (1): 7-18

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


 Bio395; Graduate Genetics course

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