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Professor of PathologyHarvard Medical School Associate Scientific DirectorMassachusetts General Hospital Cancer Center James & Patricia Poitras Endowed Chair for Cancer Research
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 thegenome. 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.
Lee Zou, PhDPrincipal Investigator
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 not only important for sensing DNA damage and replication stress, but alsofor 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. During the past few years, our studies have identified a number of novelroles that ATR plays in protecting the genome, such as: suppressing single-stranded DNA (ssDNA) accumulationduring DNA replication, regulating homologous recombination (HR), and promoting alternative lengthening of telomeres (ALT). This year, 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).
This image shows that GFP-tagged RNaseH1 (green) localizes to sites of R loops (red) through binding to RPA. R loops are transcription intermediates that contain RNA:DNA hybrids and single-stranded DNA (ssDNA). RPA is a protein complex that recognizes ssDNA. RNaseH1 is an enzyme that suppresses R loops by cleaving the RNA in RNA:DNA hybrids. Wild-type RNaseH1 recognizes R loops through binding to RPA, but the R57A mutant of RNaseH1, which is defective for RPA binding, fails to recognize R loops.
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 discovered that APOBEC3A/B proteins, two cytidine deaminases that are aberrantlyexpressed in multiple types of cancers, induce DNA replication stress and render cancer cells susceptibleto ATR inhibition. Furthermore, the splicing factor mutantsfound in 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 possiblyother malignancies associated with RNA splicing defects.
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: email@example.com
View a list of publications by researchers at the Zou Laboratory
Nguyen, HD, Leong, WY, Li W, Walter M, Zou L, and Graubert T. (2018) Spliceosome mutations in myelodysplastic syndrome induce R loop-associated sensitivity to ATR inhibition. Cancer Res. (July 27, 2018; Epub ahead of print.)
Kabeche, L., Nguyen, H. D., Buisson, R., and Zou, L. (2018) A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science 359:108-114.
Buisson, R, Lawrence MS, Benes CH, and Zou, L. APOBEC3A and 3B activities render cancer cells susceptible to ATR inhibition. Cancer Res. (July 11, 2017, Epub ahead of print).
Nguyen HD, Yadav T, Giri S, Saez B, Graubert TA, and Zou, L. (2017) Functions of RPA as a Sensor of R Loops and a Regulator of RNaseH1. Mol. Cell 65:832-847.
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. (2015) Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science. 347:273-7.
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. 471:532-6.
MGH Cancer Center Massachusetts General Hospital 149 13th Street, 7th Floor Charlestown, MA 02129 Phone: 617-724-9534 Fax: 617-726-7808
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