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Lee Zou, PhDProfessor of PathologyHarvard Medical SchoolAssociate Scientific DirectorMGH Cancer CenterJim & Ann Orr MGH Research Scholar
Cancer is a complex disease associated with 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 addicted to specific 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.
DNA damage sensing and checkpoint activation
The ATM checkpoint is primarily activated by double-stranded DNA breaks, whereas the ATR checkpoint responds to a broad spectrum of DNA damage. To understand how ATM and ATR are activated, we sought to identify the key DNA structural elements that activate ATM and ATR as well as to identify the sensor proteins that recognize these DNA structures. We have developed unique biochemical systems to mechanistically dissect the process of ATR and ATM activation. Using both proteomic and genomic approaches, we have identified a number of key regulators of the ATR checkpoint. We are extending our studies to investigate how ATR and ATM are regulated in different biological contexts, such as in response to various types of oncogenic stress, in radioresistant cancer cells, and during cellular aging.
Checkpoint, telomeres and the cell cycle
Telomere is a special DNA-protein structure formed at the ends of chromosomes. Dysfunctional telomeres have been linked to both cancer and aging. We have developed new biochemical assays to understand the interplay between checkpoint sensors and telomere-capping proteins at telomeres. Using these assays, we found that the dynamics between the two protein groups is regulated during the cell cycle. Our recent studies have revealed that the regulation of ATR checkpoint at telomeres is altered in a subset of cancers, offering an opportunity for targeted cancer therapy.
Checkpoint signaling and epigenetic regulation
The signaling of DNA damage through the checkpoint pathway is generally viewed as a cascade of protein phosphorylation events. However, several other types of protein modifications—such as ubiquitylation, SUMOylation, methylation and acetylation—are also regulated by DNA damage. Furthermore, noncoding RNAs have also been implicated in the DNA damage response. We have recently identified a number of proteins that may link these regulatory mechanisms to DNA damage response. Our ongoing studies aim to elucidate how this network of regulatory events is integrated in the presence of DNA damage.
Checkpoint inhibition 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 elevated genomic instability within them. Interestingly, we found that due to the different oncogenic stress in cancer cells, different cancers are addicted to different checkpoint signaling proteins. We are investigating how oncogenic stress leads to checkpoint addiction, aiming to exploit the checkpoint addiction of cancer cells in targeted therapy.
Read more about the Zou Lab from the Center for Cancer Research Annual Report and the Pathology Basic Science Research Brochure.
Lee Zou, PhDPrincipal Investigator
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, PhDE-mail: firstname.lastname@example.org
Wu, C., Ouyang, J., Mori, E., Nguyen, H. D., Marechal, A., Hallet, A., Chen, D. J., and Zou, L. (2014) SUMOylation of ATRIP Potentiates DNA Damage Signaling by Boosting Multiple Protein Interactions in the ATR Pathway. Genes & Dev. 28:1472-84.
Marechal, A., Li. J. M., Ji, J., Wu, C., Yazinski, S. A., Nguyen, H. D., Liu, S., Jimenez, A. E., Jin, J., and Zou, L. (2014) PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin circuitry. Mol. Cell 53:235-246.
Centore, RC, Yazinski SA, Tse A, Zou L. (2012) Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response. Mol Cell. 46:625-635.
Liu S, Shiotani B, Lahiri M, Maréchal A, Tse A, Leung CC, Glover JN, Yang XH, Zou L. (2011) ATR autophosphorylation as a molecular switch for checkpoint activation. Mol Cell. 43(2):192-202.
Flynn RL, Centore RC, O'Sullivan RJ, Rai R, Tse A, Songyang Z, Chang S, Karlseder J, Zou L. (2011) TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA. Nature. 471(7339):532-6.
Centore RC, Havens CG, Manning AL, Li JM, Flynn RL, Tse A, Jin J, Dyson NJ, Walter JC, Zou L. (2011) CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol Cell. 40(1):22-33.
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