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Professor of PathologyHarvard Medical School Associate Scientific DirectorMassachusetts General Hospital Cancer Center James & Patricia Poitras Endowed Chair for Cancer Research
Genomic instability is one of the hallmarks of cancer. On one hand, the genomic instability of cancer cells fuels tumorigenesis. On the other hand, the genomic instability of cancer cells offers a unique vulnerability that can be exploited therapeutically. While radiotherapy and chemotherapy have been successfully used to kill cancer cells with genomic instability, their cytotoxicity in normal cells presents a major challenge to cancer therapy today. The research of Dr. Zou’s laboratory is focused on understanding how genomic instability arises in cancer cells, and how it can be targeted selectively and effectively in cancer therapy. In particular, Dr. Zou and colleagues have extensively characterized the DNA damage checkpoint, a pathway that detects and signals various types of problems in the genome. Dr. Zou’s work has identified the critical sensors of DNA damage in human cells, and elucidated how these sensors activate the ATR kinase, a master regulator of the DNA damage response. The findings by Dr. Zou and colleagues have shed important light onto a fundamental cellular process that is critical for both tumor suppression and cancer therapy.
The recent and ongoing studies in Dr. Zou’s laboratory have provided new opportunities for targeted cancer therapy. They find that activation of the alternative telomere-lengthening (ALT) pathway in a subset of cancers renders tumor cells hypersensitive to ATR inhibitors. Several cancer types, including various sarcomas, pediatric and high-grade glioblastomas, and neuroendocrine pancreatic tumors, are prevalent for ALT. In collaboration with Dr. Miguel Rivera, a pathologist, Dr. Zou’s lab is developing a new assay for identifying ALT tumors. These studies may lead to new clinical trials for the treatment of ALT tumors with ATR inhibitors. Recent studies from the Zou lab also reveal that ATR inhibitors are able to selectively kill cancer cells under high levels of DNA replication stress. Importantly, their studies identified single-stranded DNA (ssDNA) as a general indicator of replication stress, which may provide a useful biomarker for the use of ATR inhibitors in targeted cancer therapy. These and other studies in the Zou lab have highlighted the value of the ATR checkpoint pathway as a therapeutic target, bringing about a new way to exploit the genomic instability and DNA repair dependency in cancer cells with increased selectivity and efficacy.
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
FellowsRemi Buisson, PhD Marie, Michelle Genois, PhDSumanprava Giri, PhDLilian Kabeche, PhDDavid Moquin, PhD Hai Dang Nguyen, PhD Jian Ouyang, PhD Tribhuwan Yadav, PhD Stephanie Yazinski, PhDGRADUATE STUDENTDominick Matos, PhD student
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 the ATR checkpoint kinase regulates the recruitment of PALB2 to sites of DNA damage. Cells were irradiated with ionizing radiation (IR) and analyzed for the localization of BRCA1 (red) and PALB2 (green). Both BRCA1 and PALB2 are key proteins for homologous recombination, a crucial DNA repair pathway in human cells. In cells treated with ATR inhibitor (ATRi), PALB2 was no longer localized to DNA damage-induced nuclear foci.
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.
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
Yazinski, A. S., and Zou, L. (2016) Functions, Regulations and Therapeutic Implications of the ATR Checkpoint Pathway. Annu Rev Genet. (In press)
Buisson R, Boisvert JL, Benes CH, and Zou L. (2015) Distinct but Concerted Roles of ATR, DNA-PK and Chk1 in Countering Replication Stress during S Phase. Mol. Cell 59:1011-24.
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.
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. (2014) SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes Dev. 28:1472-84.
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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