research research research-lab cancer-center;pathology z true

Zou Lab

Our goal is to understand the underlying principles of cellular responses to chromosomal insults and their roles in the maintenance of genomic stability.
lee zou
lee zou

Explore the Zou Lab

Research Summary

Cancer is a complex disease driven by genetic and epigenetic alterations in the genome. To prevent these detrimental alterations, cells have evolved an intricate signaling network, called the DNA damage checkpoint, to detect and signal problems in the genome. During cancer development, the activation of oncogenes and loss of tumor suppressors leads to genomic instability, rendering cancer cells increasingly dependent upon specific DNA repair and checkpoint signaling proteins to survive. The Zou laboratory is particularly interested in understanding how the checkpoint detects DNA damage and genomic instability, and how the checkpoint can be targeted in cancer therapy. Our current studies are focused on the activation of ATR and ATM, the master sensor kinases of two major checkpoint pathways. Furthermore, we are developing new strategies to exploit the genomic instability and checkpoint addiction of different cancer cells in targeted cancer therapy.

Read more about the Zou Lab from the Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.

Research Projects

Sensing of DNA Damage, Replication, Stress, and Transcription Problems

ATM and ATR are two master checkpoint kinases in human cells. In particular, ATR is the key responder to a broad spectrum of DNA damage and DNA replication problems. To understand how ATR is activated, we sought to identify the key DNA structural elements and sensor proteins that activate ATR. We have developed unique biochemical and cell biological assays to dissect the process of ATR activation. Our recent studies have revealed that ATR is important not only for sensing DNA damage and replication stress, but also for problems associated with transcription. R loops, which arise from stable DNA:RNA hybrids during transcription, are a major source of genomic instability. We found that ATR is activated by R loops and plays a key role in suppressing R loop-induced genomic instability, thus, uncovering a new function of ATR in safeguarding the genome.

Checkpoint, DNA Replication, DNA Repair, Telomeres, Centromeres and the Cell Cycle

The ATR checkpoint plays a key role in regulating and coordinating DNA replication, DNA repair, and cell cycle transitions. Recently, we have discovered a surprising function of ATR in mitosis. We have shown that ATR is localized to centromeres in mitosis, where it is activated by centromeric R loops. The activation of ATR at centromeres is critical for faithful chromosome segregation, thus revealing the unexpected importance of ATR in suppressing chromosomal instability (CIN). We have also developed new assays to understand how the alternative lengthening of telomere (ALT) pathway, which is regulated by ATR, is activated at telomeres. These new assays have helped us establish the framework of the ALT pathway for the first time, and uncovered the key mechanisms by which the ALT pathway is temporarily and spatially regulated during the cell cycle.

RNA, DNA repair and Genomic Integrity

We are interested in the impacts of RNAs, including coding and non-coding RNAs, on genomic integrity. TERRA, a non-coding RNA arising from telomeres, plays an important in ALT. We have developed new cellular and biochemical assays to interrogate the functions of TERRA in ALT, allowing us to reveal how this non-coding RNA regulates DNA recombination at telomeres. We have also developed new assays to investigate how RNA transcripts regulate homologous recombination at DNA breaks in transcribed regions. These assays have enabled us to discover surprising mechanisms by which RNAs directly participate in DNA repair. These new findings will significantly change the current view of the functions of RNAs in DNA repair, providing new opportunities for cancer therapy.

Cancer Genomics, Tumor evolution and Targeted Cancer Therapy

During the evolution of tumors, cancer cells acquire mutations through a variety of mechanisms. We recently discovered that APOBEC3A/B proteins, two cytidine deaminases that are aberrantly expressed in multiple types of cancers, induce DNA replication stress and render cancer cells susceptible to ATR inhibition. Working with the team of Dr. Michael Lawrence, we find that APOBEC3A prefers substrate sites in DNA hairpins, leading to the discovery of passenger hotspot mutations in cancer. Furthermore, in collaboration with Dr. Tim Graubert, we find that the splicing factor mutations associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) induce R loops and trigger an ATR response. Cells that express these splicing factor mutants are sensitive to ATR inhibitors, providing a new strategy for the treatment of MDS and possibly other malignancies associated with RNA splicing defects.

Research Positions

Postdoctoral Position (1)

A postdoctoral position is available to study DNA damage checkpoint signaling and regulation of DNA repair and replication. Our research is aim at understanding how cells sense DNA damage and orchestrate various damage responses to maintain genomic stability (PNAS 25:13827-32; Science 300:1542-49; G&D 16: 198-208.). We are currently using biochemical, cell biological, and genetic approaches to investigate how the ATR-mediated checkpoint is activated by DNA damage and how it coordinates DNA synthesis and repair at stalled replication forks. Both human cells and budding yeast, two highly complementary model systems, are being used as in our studies. Interested applicants should have a PhD and/or MD degree, and a strong background in either biochemistry, cell biology, or yeast genetics.

To apply, please send a CV with past research experience and contact information of three references to:

Lee Zou, PhD


View a list of publications by researchers at the Zou Laboratory

Selected Publications

Jalili P, Bowe, B, Langenbucher A, Park S, Aguirre K, Corcoran RB, Fleischman A, Lawrence MS*, Zou L*, Buisson R*. Quantification of ongoing APOBEC3A activity in tumor cells by monitoring RNA editing at hotspots. Nat Commun. 2020 Jun 12;11(1):2971.

Matos, D. A., Zhang, J., Ouyang, J., Nguyen, H. D., Genois, M.-M., and Zou, L.  ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop. Mol. Cell 2020 Feb 6;77(3):514-527.e4.

Buisson R, Langenbucher A, Bowen D, Kwan EE, Benes CH, Zou L*, and Lawrence SM*. Passenger Hotspot Mutations in Cancer Driven by APOBEC3A and Mesoscale Genomic Features. Science 2019 Jun 28;364(6447):eaaw2872.

Zhang JM, Yadav T, Ouyang J, Lan L, Zou L. Alternative Lengthening of Telomeres through Two Distinct Break-Induced Replication Pathways. Cell Rep. 2019 Jan 22;26(4):955-968.e3.

Moquin MD, Buisson R, Genois MM, Ouyang J, Yadav T, Boukhali M,. Morris R, Haas W, and Zou L. Localized Protein Biotinylation Identifies ZPET, a Repressor of Homologous Recombination. Genes & Dev. 2019 Jan 1;33(1-2):75-89.

Kabeche, L., Nguyen, H. D., Buisson, R., and Zou, LA mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science 2018, 359:108-114.

*Co-corresponding authors

Research Image: Telomeric bridges in an ALT+ cancer cell lacking the BLM helicase.

Alternative lengthening of telomere (ALT) is a recombination-based mechanism to extend telomeres in cancer cells. We find that the BLM helicase is critical for resolving telomere recombination intermediates in ALT+ cancer cells. In the absence of BLM, unresolved recombination intermediates at telomeres result in chromosomal bridges in mitosis.

Our Researchers

Lee Zou, PhD

Principal Investigator

Group Members

  • Brian Brannigan
  • Ethan Doiron Laurue
  • Marie-Michelle Genois, PhD
  • Jessica Hopkins, PhD
  • Rosaline Yuan-Chieh Hsu, PhD
  • Donald Johnston*
  • Ajinkya Kawale, PhD
  • Jacob Peter Matson, PhD
  • Jian Ouyang, PhD
  • Sneha Saxena, PhD
  • Antoine Simoneau, PhD
  • Tribhuwan Yadav, PhD
  • Takaaki Yasuhara, PhD
  • Jiamin Zhang, PhD
* Undergraduate student