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MILLER, KYLE M

Kyle M Miller

Associate Professor
Molecular Biosciences


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

kyle.miller@austin.utexas.edu


Office Location
NMS 4.306

Postal Address
The University of Texas at Austin
NEURAL MOLECULAR SCIENCE
2506 SPEEDWAY, Stop A5000
AUSTIN, TX 78712-1191

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 (out of 50):

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 C1Miller KM1and Rosenberg SM1. Bacteria-to-human protein networks reveal origins of endogenous DNA damageCell. 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

 

2016-2020       Research Scholar of the American Cancer Society

2015                W.M. Keck FoundationAward (Co-PI)

2011-2017       Institute for Cellular and Molecular Biology Fellowship, University of Texas at Austin

2011-2015       CPRIT Scholar; The Cancer Prevention and Research Institute of Texas

INVITED TALKS (total 71)

Conference Presentations

2018  “One Genome Many Functions – Involvement of Chromatin and DNA damage-up Proteins in Genome Maintenance”. Dec 8th,ASCB-EMBO, San Diego, California.

2018  “The DNA damage Response: Chromatin and Cancer”. July. 21st,ASCB FRED Workshop, Chicago, Illinois.

2018  “Chromatin Regulation of Genome and Epigenome Stability”. Jun. 27th,Gordon Research Conference: Mutagenesis, Newry, Maine.

2018  “Chromatin-based mechanisms of DSB repair”. Jun. 4th,EMBO Workshop: Chromatin dynamics and nuclear organization in genome maintenance, Illkirch, France.

2018  “Chromatin-based mechanisms of genome maintenance”. Mar. 23rd,45thAnnual Texas Genetics Society Meeting, Texas A&M, College Station, Texas.

2017 “Bromodomain proteins: Readers of Genome Integrity”. Oct 30th,Protecting the Code: Epigenetic Impacts on Genome Stability, EACR meeting,Berlin, Germany. 

2017  “Bromodomain proteins: Epigenetic readers in the DNA damage response and cancer”. Oct 28th,Epigenetic Mechanisms in Health and Disease, B-Debate meeting,Barcelona, Spain. 

2017 “Chromatin Regulation of the DNA Damage Response”. April 4th. Genomic Instability and DNA Repair Keystone Symposium, Santa Fe, New Mexico.

2017   “Regulation of DNA Repair Within the Chromatin Environment”. Feb.  23rdMammalian DNA   Repair, Gordon Conference. Ventura, CA.

2016 “Coordination of Transcription and DNA Damage Responses by Chromatin”. Mar 29th,Chromatin, Non coding RNAs and RNAP II Regulation in Development and Disease, Abcam Conference, Austin, TX.

2016  “Reprogramming the epigenome to kill cancer cells with DNA-targeting drugs”. Mar 8th,Genome Stability, Abcam Conference, Panama City, Panama.

2016 “Reprogramming the epigenome to kill cancer cells with DNA-targeting drugs”. Feb 5th,Baylor College of Medicine/MD Anderson Cancer Center Joint Symposium “DNA Damage Response and Cancer Therapy”. Houston, TX.

2015   "Bromodomain Chromatin Reader Proteins: Guardians of Genome and Epigenome Integrity". Sept 28th,Environmental Mutagenesis and Genomics Society Annual Meeting.New Orleans, LA.

2015 "Regulation of DNA double-strand break repair via homologous recombination by the histone variant macroH2A". July 23rd,FASEB Genetic Recombination and Genome RearrangementsSteamboat Springs, CO.

2015 "Regulation of DNA repair by histone marks, variants and chromatin reader proteins in human                      cells". June 3nd,IMB Conference. DNA Repair & Genome Stability in a Chromatin                                 Environment.Mainz, Germany.

2015 "Chromatin Reader proteins: Linking Chromatin tothe DNA Damage Response". April 16th,NCI Chromosome Biology Symposium “Chromatin, ncRNA, Methylation & Disease”. National Institutes of HealthBethesda, Maryland.

2015  “Screen Identifies Role for Bromodomain Chromatin Reader Proteins in the DNA Damage

Response”. March 4th. Genomic Instability and DNA Repair Keystone Symposium, Whistler, Canada.

2015 “ATM Links Endogenous Oxidative Stress to Tumor Promotion”. Feb 13thExploring DNA Repair Pathways as Targets for Cancer Therapy, Fusion Conference,Cancun, Mexico.

2014 “Chromatin and the DNA damage response”. Nov 22ndU.S.-China Physical Sciences-Oncology Alliance, Phoenix, AZ. 

2014  “Bromodomain Proteins: Linking Chromatin to the DNA Damage Response”. June 12th, Chromatin Structure and Function Gordon Conference, Waltham, MA.

2014 “Nucleosome acidic patch promotes H2AX and H2A ubiquitination and DNA damage signaling”. April 30th, Experimental Biology Meeting, San Diego, California.

2014 “Nucleosome acidic patch promotes H2AX and H2A ubiquitination and DNA damage signaling”. Mar 6th, Genome Stability, Abcam Conference, St. Kitts.

2013 “Systematic identification of functional residues in mammalian histone H2AX”. March 4th. Genome Instability and DNA repair, Keystone Symposium, Banff, Canada.

2013 “Systematic identification of functional residues in mammalian histone H2AX”. Feb 13th, Mammalian DNA repair, Gordon Conference, Ventura, CA.

2012 “Systematic identification of functional residues in mammalian histone H2AX”. Nov 4th, Genetics and Epigenetics of Genome Integrity Lost Pines Conference. MD Anderson Science Park, Smithville, Texas. 

 

Seminars

2018                John Hopkins University, Baltimore, MD. Host: Urbain Weyemi. (Nov 15)

2018                University of North Carolina Charlotte, Charlotte, NC. Host: Shan Yan. (Oct 19)

2018                Mayo Clinic, Rochester, MN. Host: Zhenkun Lou. (Oct 12)

2018                University Laval, Quebec City, Canada. Host: Amelie Fradet-Turcotte. (Oct 5)

2018                Institute of Human Genetics (IGH). Montpellier, France. Host: Angelos Constantinou. (Sept 14)

2018                 Ohio State University. Host: Joanna Groden. (July 9)

2018                New York University. Host: Michele Pagano. (May 22)

2018                University of Vermont. Host: David Pederson. (Feb 14)

2017                University of Pennsylvania. Host: Matt Weitzman. (Nov 27)

2017                Chinese Academy of Sciences, Beijing, China. Host: Chunsheng Han. (Nov 14)

2017                IRC, London, England. Host: Jessica Downs. (April 13)

2016                TheSalk Institute. Host: Jan Karlseder. (April 13)

2016                UNC Chapel Hill, Lineberger Cancer Center. Host: Brian Strahl. (April 13)

2016                IRB, Barcelona, Spain. Host: Travis Stracker. (April 13)

2016                Gulbenkian Institute, Lisbon, Portugal. Host: Miguel Ferreira. (April 13)

2016                Memorial Sloan-Kettering, New York, NY. Host: Iestyn Whitehouse. (April 13)

2016                University of British Columbia, Victoria, Canada. Host: Chris Nelson. (April 13)

2016                City of Hope, Los Angeles, CA. Host: Jeremy Starks. (April 13)

2016                University of Southern California, Los Angeles, CA. Host: Judd Rice. (April 13)

2016                University of Colorado Medical School, Denver, CO. Host: Bob Sclafani. (Feb 4)

2016                University of Zurich, Zurich, Switzerland. Host: Petr Cejka. (Jan 29)

2016                EPFL, Lausanne, Switzerland. Host: Beat Fierz. (Jan 27)

2016                Curie Institute, Paris, France. Host: Raphael Rodriguez. (Jan 25)

2016                Gurdon Institute, University of Cambridge, United Kingdom. Host: Rafael Carazo Salas. (Jan 21)

2015                Lunenfeld-Tanenbaum Research Inst., U. of Toronto, Canada. Host: Dan Durocher. (Aug 20)

2015                CRUK/MRC Oxford Inst. for Radiation Oncology, UK Host: Tim Humphrey. (June 9)

2015                LUMC, Department Human Genetics, Leiden, Netherlands. Host: Haico Van Attikum. (June 2)

2015                 National Institutes of Health, Bethesda, Maryland. Host: Phillip Oberdoerffer.(April 15)

2015                University of Pittsburgh, School of Medicine, Pittsburgh, PA. Host: Kara Bernstein.(Jan 7)

2013                National Institutes of Health, Bethesda, Maryland. (May 8)

2013                Dept. of Biochemistry Seminar Series. Baylor College of Medicine, Houston, Texas. (April 18)

2013                Scripps Research Institute, La Jolla, CA. Host: Eros Denchi.(Feb 15)

2012                Department of Pharmacy and Toxicology Seminar Series. University of Texas at Austin. Host: Karen Vasquez.(Nov 15)

2012                Department of Genetics Seminar Series. Baylor College of Medicine, Houston, Texas. Host: Susan Rosenberg.(Aug 28)

2012                MD Anderson Cancer Center and Baylor College of Medicine, Genome Instability Group, Houston, Texas. Host: Jessica Tyler and Grzegorz Ira. (April 13)          

2012                MD Anderson Science Park, Smithville, Texas. Host: David Johnson. (Jan 23)

2011                University of Toulouse, France. Host: Gaelle Legube. (March 28)

2010                London Research Institute at Clare Hall, Cancer Research, UK. (Aug 19)

2010                Genes to Cells seminar series, London Research Institute, Cancer Research, UK. (June 25)

 Bio395; Graduate Genetics course

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