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Read the Zou Lab 2017-2018 Annual Report
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 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.
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 found that BRCA1/2 deficient cancer cells became resistant to PARP inhibitors through bypassing the functions of BRCA1/2 in homologous recombination (HR) and protection of stalled replication forks. Remarkably, inhibition of ATR disrupts the rewired HR and fork protection pathways in resistant cells, resensitizing them to PARP inhibitors. Our findings may bring about a new strategy to overcome the resistance of BRCA deficient tumors to PARP inhibitors.
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
View a list of publications by researchers at the Zou Laboratory
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.
Yazinski AS, Comaills V, Buisson R, Genois MM, Nguyen HD, Ho CK, Todorova Kwan T, Morris R, Lauffer S, Nussenzweig A, Ramaswamy S, Benes CH, Haber DA, Maheswaran S, Birrer MJ, and Zou L. (2017) ATR Inhibition disrupts Rewired Homologous Recombination and Fork Protection Pathways in PARP Inhibitor-resistant BRCA-Deficient Cancer Cells. Genes & Dev. 31:318-332.
Buisson R, Joshi N, Rodrigue A, Ho CK, Kreuzer J, Foo TK, Hardy E, Dellaire G, Hass W, Xia B, Masson J, and Zou L. (2017) Coupling of Homologous Recombination and the Checkpoint by ATR. Mol. Cell. 65:336-346.
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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