Zou Lab

Research topics include: DNA damage response; DNA damage checkpoint; checkpoint signaling; checkpoint activation; genomic instability


Lee Zou, PhD
Professor of Pathology
Harvard Medical School

Associate Scientific Director
MGH Cancer Center
Jim & Ann Orr MGH Research Scholar

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 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.


Pathology logo and research brochure

Group Members

Lee Zou, PhD
Principal Investigator

Group Members

  • Remi Buisson, PhD
  • Alexander Hallet  
  • Alexandre Marechal, PhD
  • Dominick Matos
  • Hai Dang Nguyen, PhD
  • Jian Ouyang, PhD    
  • Ching-Shyi Wu, PhD  
  • Tribhuwan Yadav, PhD
  • Stephanie Yazinski, PhD


Research Projects

Sensing and signaling of DNA damage

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. Using both proteomic and genomic approaches, we have identified a number of regulators of the ATR checkpoint and novel functions of this pathway. We are currently investigating the regulation of ATR in different physiological, pathological and therapeutic contexts, such as in response to oncogenic stress, in radiation and drug resistant cancer cells, and during cellular aging. 

Checkpoint, DNA replication, DNA repair, telomeres and the cell cycle

The ATR checkpoint plays a key role in regulating and coordinating DNA replication, DNA repair, and cell cycle transitions. To understand these functions of ATR, we have identified new substrates of ATR involved in each of the processes. Furthermore, we are using a systems approach to interrogate how ATR orchestrates the network of DNA damage responses in different contexts. Our lab is also exploring the novel functions of ATR at specific chromosomal loci, such as telomeres and fragile sites. These studies may significantly advance our understanding of how the genome is safeguarded during the cell cycle.

Checkpoint signaling, non-coding RNA, and epigenetic regulation

The signaling of DNA damage through the checkpoint pathway is generally viewed as a cascade of protein phosphorylation events. However, recent studies by us and others have revealed that many types of modifications of proteins and chromatin—such as ubiquitylation, SUMOylation, methylation and acetylation—also contribute to DNA damage signaling. Furthermore, noncoding RNAs have also been implicated in this process. We are currently investigating how this network of regulatory events is integrated to the DNA
damage response.

Checkpoint inhibitors and targeted cancer therapy

While the checkpoint is often compromised in cancers, certain checkpoint proteins are uniquely required for the survival of cancer cells because of the oncogenic events within them. We recently found that cancer cells reliant on the alternative telomere-lengthening (ALT) pathway are hypersensitive to ATR inhibitors. ALT is active in 10-15% of human cancers, and prevalent in sarcomas, glioma and pancreatic cancer. Our findings may provide a new strategy for the treatment of these cancers.

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.


Please send a CV with past research experience and contact information of three references to:

Lee Zou, PhD
E-mail: leezou@rics.bwh.harvard.edu


View a list of publications by researchers at the Zou Laboratory

Selected Publications

Buisson R, Boisvert JL, Benes CH, and Zou L. Distinct but Concerted Roles of ATR, DNA-PK and Chk1 in Countering Replication Stress during S Phase. Mol. Cell (in press).

Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suvà ML, Benes CH, Haber DA, Boussin FD, Zou L. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 2015 Jan 16;347(6219):273-7.

Ouyang J., Garner E., Marechal A., Hallet A., Rickman K. A., Gill G., Smogorzewska A., and Zou L. (2015) Non-covalent Interactions with SUMO and Ubiquitin Orchestrate Distinct Functions of the SLX4 Complex in Genome Maintenance. Mol. Cell 57:108-122.

Wu CS, Ouyang J, Mori E, Nguyen HD, Maréchal A, Hallet A, Chen DJ, Zou L. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes Dev. 2014 Jul 1;28(13):1472-84.

Maréchal A, Zou L. RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response. Cell Res. 2015 Jan;25(1):9-23.

Flynn RL, Centore RC, O’Sullivan RJ, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L. TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 2011 Mar 24;471(7339):532-6.


Contact Us

Zou Laboratory

7th FloorBldg 149, 13th Street Charlestown, MA 02129

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