Breadcrumb

Yves  Pommier, M.D., Ph.D.

Yves Pommier, M.D., Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
  • Building 37, Room 5068
  • Bethesda, MD 20892-4255
  • 240-760-6142
  • pommier@nih.gov

RESEARCH SUMMARY

Dr. Pommier is a leader on DNA topoisomerase biology and biochemistry, and their cancer relevance. He revealed the interfacial inhibition paradigm based on molecular mechanisms of topoisomerase inhibitors, and has championed its broad relevance for molecular pharmacology and drug discovery. He discovered the indenoisoquinolines as novel Top1 inhibitors, which are in clinical development, and the mitochondrial topoisomerase gene, TOP1mt. To understand the determinants of response to topoisomerase inhibitors, he is studying the repair pathway centered on tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2) and poly(ADP-ribose)polymerases (PARP).

As Chief, Dr. Pommier oversees the Branch’s clinical/translational research program, which emphasizes new approaches to cancer treatments targeting DNA, epigenetic and chromatin, and connected biomarkers.

Areas of Expertise

1) topoisomerases, 2) molecular pharmacology, 3) DNA repair, 4) HIV integrase, 5) drug screening. 6) genomics in relationship with therapeutics response and anticancer drug activity

Publications

Selected Recent Publications

Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes.

Huang, S.-y.N., Michaels, S.A., Mitchell, B.B., Majdalani, N., Vanden Broeck, A., Canela, A., Tse-Dinh, Y.-C., Lamour, V., and Pommier Y.
Science Advances . 7(10): eabe0384, 2021. [ Journal Article ]

SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors.

Jo, U., Murai, Y., Chakka, S., Chen, L., Cheng, K., Murai, J., Saha, L.K., Miller Jenkins, L.M., and Pommier
Proceedings of the National Academy of Sciences. 118: e2015654118, 2021. [ Journal Article ]

CellMiner Cross-Database (CellMinerCDB) version 1.2: Exploration of patient-derived cancer cell line pharmacogenomics.

Luna, A., Elloumi, F., Varma, S., Wang, Y., Rajapakse, V.N., Aladjem, M.I., Robert, J., Sander, C., Pommier, Y., and Reinhold,W.C.
Nucleic Acids Res. 49(D1): D1083-D1093, 2021. [ Journal Article ]

Replication-dependent cytotoxicity and Spartan-mediated repair of trapped PARP1–DNA complexes.

Saha, L.K., Murai, Y., Saha, S., Jo, U., Tsuda, M., Takeda, S., and Pommier, Y.
Nucleic Acids Research.. 10: 1093/nar/gkab777, 2021. [ Journal Article ]

PARylation prevents the proteasomal degradation of topoisomerase I DNA-protein crosslinks and induces their deubiquitylation.

Sun, Y., Chen, J., Huang, S.N., Su, Y.P., Wang, W., Agama, K., Saha, S., Jenkins, L.M., Pascal, J.M., and Pommier, Y.
Nat Commun. 12(1): 5010., 2021. [ Journal Article ]

Job Vacancies

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Team

Technical Laboratory Manager
Keli K. Agama, Ph.D.
Postdoctoral Fellow (Visiting)
Andrea Baechler, Ph.D.
Sifan Banig
Clinical Program Coordinator (gov.)
Sifan Banig, B.S.
Special Volunteer
Valentina Factor, Ph.D.
Staff Scientist
Shar-Yin Huang, Ph.D.
Postdoctoral Fellow (Visiting)
Ukhyun Jo, Ph.D.
Staff Scientist
Natalay Y. Kouprina, Ph.D.
Staff Scientist
Suresh Kumar, Ph.D.
Research Collaborator
Augustin Luna, Ph.D.
Postdoctoral Fellow (Visiting)
Yasuhisa Murai, Ph.D.
Research Microbiologist
Ann H. Orr, Ph.D.
Postdoctoral Fellow (Visiting)
Lorinc Pongor, Ph.D.
Postdoctoral Fellow (Visiting)
Liton Kumar Saha, Ph.D.
Postdoctoral Fellow (Visiting)
Sourav Saha, Ph.D.
Postdoctoral Fellow (Visiting)
Yilun Sun, Ph.D.
Postdoctoral Fellow (Visiting)
Wenjie Wang, Ph.D.
Postdoctoral Fellow (Visiting)
Xi Yang, Ph.D.
Staff Scientist
Hongliang Zhang, Ph.D.

Covers

iScience cover, December 21, 2018

CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines

Published Date

About the Cover:  Drugs and Genomic databases are directly accessible using the web-based CellMinerCDB resource (https://discover.nci.nih.gov/cellminercdb/). The drug in clinical trial LMP400 (indotecan) is represented together with a DNA molecule giving rise to genomic data, which are integrated to generate hypotheses on mechanisms of action and genomic signatures for precision medicine.

Citation

CellMinerCDB for Integrative Cross-Database Genomics and Pharmacogenomics Analyses of Cancer Cell Lines. Rajapakse VN, Luna A, Yamade M,Loman L, Varma S, Sunshine M, Iorio F, Sousa FG, Elloumi F, Aladjem MI, Thomas A, Sander C, Kohn KW, Benes CH, Garnett M, Reinhold WC, Pommier Y. iScience Dec 21; 10: 247-264, 2018.

Nature Reviews Molecular Cell Biology, Vol. 17, No. 11, November 2016

Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

Published Date

About the Cover

'DNA relaxation' by Vicky Summersby

Abstract

Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2
and by endonucleases (MRE11, XPF–ERCC1 and MUS81). Here, we review the roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability, and discuss how deregulation of topoisomerases can cause neurodegenerative diseases, immune disorders and cancer.

Citation

Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Pommier Y, Sun Y, Huang SN, and Nitiss JL. Nature Rev Mol Cell Biol  2016 Nov;17(11):703-721.

ACS Chemical Biology cover - Vol. 11, No. 2, Apr. 15, 2016

HIV‑1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

Published Date

On the cover: Mutant forms of HIV-1 IN reduce the therapeutic effectiveness of integrase strand transfer inhibitors (INSTIs). The cover figure shows the IN of prototype foamy virus complexed to a novel INSTI (gold) that retains potency against resistant mutants of HIV-1 IN. Overlain are the host and viral DNA substrates (blue and green, respectively), showing substrate mimicry by the inhibitor.

Cover design by Joseph Myer

Citation

Xue Zhi Zhao, Steven J. Smith, Daniel P. Maskell, Mathieu Metifiot, Valerie E. Pye, Katherine Fesen, Christophe Marchand, Yves Pommier, Peter Cherepanov, Stephen H. Hughes and Terrence R. Burke, Jr. in ACS Chemical Biology, 20165, 11 , 1074-1081.

ACS Chemical Biology cover - Vol. 11, No. 7, July 2016

Inhibition of human TDP2 by deazaflavins

Published Date

Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively inhibit the human TDP2 enzyme in a competitive manner both with recombinant and native TDP2. We show that mouse, fish, and C. elegans TDP2 enzymes are highly resistant to the drugs and that key protein residues are responsible for drug resistance. Among them, human residues L313 and T296 confer high resistance when mutated to their mouse counterparts. Moreover, deazaflavin derivatives show potent synergy in combination with the topoisomerase II inhibitor etoposide in human prostate cancer DU145 cells and TDP2-dependent synergy in TK6 human lymphoblast and avian DT40 cells. Deazaflavin derivatives represent the first suitable platform for the development of potent and selective TDP2 inhibitors.

Citation

Deazaflavin inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2) specific for the human enzyme and active against cellular TDP2. Marchand C, Abdelmalak M, Kankanala J, Huang SY, Kiselev E, Fesen K, Kurahashi K, Sasanuma H, Takeda S, Aihara H, Wang Z, Pommier Y. ACS Chem Biol. 2016 Jul 15;11(7):1925-33.