Nancy Maizels, Ph.D.

Nancy Maizels, Ph.D.

Professor, Immunology and Biochemistry; Adjunct Professor, Pathology; Director, Molecular Medicine Program

Dr. Maizels was an undergraduate at the University of California at Berkeley. She received her Ph.D. from Harvard University, and she continued at Harvard as a Junior Fellow of the Society of Fellows. She was a Professor in the Departments of Molecular Biophysics & Biochemistry and Genetics at Yale University School of Medicine before coming to the University of Washington in Fall, 2000.

Contact Info

Professor of Immunology and Biochemistry
Adjunct Professor of Pathology
University of Washington  
Office H474, HSC, Box 357350
1959 NE Pacific Street
Seattle WA 98195
Phone: 206.221.6876
Fax: 206.221.6781

Research Areas

  • Targeted Gene Therapy
    Genomic Instability and Cancer Therapies
    Immunoglobulin Gene Diversification

LAB

Pubmed

Nancy Maizels

Research in our laboratory builds on the conviction that molecular understanding is key to treatment of human disease.  We focus on the mechanisms that maintain and alter genomic structure and sequence, which are key to the immune response, cancer, genetic disease, and — most recently — gene therapy.  

CRISPR/Cas and other targeted endonucleases now make it possible to edit essentially any site in any genome.  The challenge is to make genome editing as efficient and safe as possible.  Nicks are the most common form of DNA damage, but their potential to cause genomic instability had been largely ignored.  Our evidence that DNA nicks (not double-strand breaks) initiate Ig gene conversion suggested that nicks could initiate homology-directed repair (HDR) in human cells.  We worked with colleagues to develop an early “nickase”, and showed HDR at nicks was efficient accompanied by far less local mutagenesis than HDR targeted by a double-strand break.  We discovered that human cells can carry out HDR at nicks using a novel alternative pathway that may be activated in solid tumors, especially breast and ovarian cancers (Davis and Maizels, 2014).  We are currently optimizing pathways of HDR to improve targeted gene therapies. 

The DNA nicks that initiate all three pathways of Ig gene diversification (somatic hypermutation, class switch recombination, and gene conversion) result from DNA deamination by a single mutagenic factor, Activation-Induced Deaminase (AID).  AID activity is essential to the human immune response, but in excess it can cause genomic instability that is evident as translocations in B cell tumors.  Key current questions are how AID is regulated and targeted.  We recently showed that cell cycle controls AID activity and its potential for cellular toxicity, with G1 phase representing the sweet spot for Ig gene diversification (Le and Maizels, 2015).  In activated B cells AID is targeted to the transcribed Ig switch regions, which form G4 (G-quadruplex) structures.  We have studied of the role of G4 DNA in genomic biology, both in Ig class switch recombination and in cancer.  Oncogenes prove to be greatly enriched in G4 motifs, which raised the possibility that G4 motifs confer added levels of regulation.  Consistent with this, we recently demonstrated that factors identified as G4 helicases, including XPB/XPD and BLM, all play dual roles as transcriptional regulators, in experiments that demonstrated by ChIP-Seq analysis that G4 DNA structures throughout the genome (p=0) are regulatory targets of transcription factors XPB/XPD (Gray et al. 2014; Nguyen et al., 2015). 

Many cancer therapies overload nuclear repair pathways to kill rapidly dividing tumor cells, in some cases by promoting formation of stable, covalent DNA-protein complexes.  We have developed a robust and quantitative assay for these complexes, the RADAR assay (Kiianitsa and Maizels, 2013, 2014).  We are applying the RADAR assay to study and optimize the response to radiation therapy and to drugs that function as topoisomerase poisons, such as irinotecan and etoposide.

Le, Q. and Maizels, N. 2015. Cell cycle regulates nuclear stability of AID and determines the cellular response to AID. PLoS Genetics 11:e1005411 (featured in a Perspective by C. Rada in the same issue).

Davis, L. and Maizels, N. 2014. Homology-directed repair of DNA nicks via pathways distinct from canonical double-strand break repair. Proc. Natl. Acad. Sci. USA 111: e924-932. 

Gray, L.T., Vallur, A.C., Eddy, J. and Maizels, N. 2014. G-quadruplexes are genomewide targets of transcriptional helicases XPB and XPD. Nature Chem. Biol. 10: 313-318. 

Nguyen, G.H., Tang, W., Robles, A.I., Beyer, R.P., Gray, L.T., Welsh, J., Schetter, A., Kumamoto, K., Wang, X. W., Hickson, I.D., Maizels, N., Monnat, R.J., Jr., Harris, C.C. 2014. Regulation of gene expression by BLM helicase correlates with the presence of G4 motifs. Proc. Natl. Acad. Sci. USA 111:9905-9910.

Maizels, N. 2015. G4-associated human diseases. EMBO Rep 16:910-922.

Kiianitsa, K. and Maizels, N. 2014. Ultrasensitive isolation, identification and quantification of DNA-protein adducts. Nucleic Acids Res. 42:e108.

Kiianitsa, K. and Maizels, N. 2013. A rapid and sensitive assay for DNA-protein covalent complexes in living cells. Nucleic Acids Res. 41:e104. 

Maizels, N.  2013. Genome engineering with Cre-IoxP. J Immunol 191:5-6.

Maizels, N. and Gray, L.T. 2013. The G4 genome. PLoS Genet 9:e1003468.

Humbert, O. and Maizels, N. 2012. Epigenetic modification of the repair donor regulates targeted gene correction. Mol. Therapy — Nucleic Acids 1:e49.

McConnell Smith, A., Takeuchi, R., Pellenz, S., Davis, L., Maizels, N., Monnat, R.J., Jr. and Stoddard, B.L. 2009. Generation of a nicking enzyme that stimulates site-specific gene conversion from the I-AniI LAGLIDADG homing endonuclease. Proc. Natl. Acad. Sci. USA 106: 5099-6104. 

Vallur, A.C. and Maizels, N. 2008. Activities of human exonuclease 1 that promote cleavage of transcribed immunoglobulin switch regions. Proc. Natl. Acad. Sci USA 105: 16508-16512.

Eddy, J. and Maizels, N. 2008. Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes. Nucleic Acids Res. 36:1321-1333.

Cummings, W.J., Yabuki, M., Ordinario, E.C., Bednarski, D.W., Quay, S. and Maizels, N. 2007. Chromatin structure regulates gene conversion. PLoS Biol. 5: e246.

A.B., Biology-Physics, University of California Berkeley
Ph.D., Biophysics, Harvard University

Graduate Students
Kevin Khoo, khook@uw.edu
Henry Olson, h5c5o5@uw.edu

Postdoctoral Fellows
Lucas Gray, ltgray@uw.edu
Quy Le, quyl@uw.edu

Laboratory Staff
Luther Davis, lwd@uw.edu
Konstantin Kiianitsa, kkiianit@uw.edu