A class of drugs used to treat breast, ovarian, prostate and other cancers selectively exploits self-repair and surveillance defects of cancer cells carrying BRCA1 and BRCA2 mutations.
149 13th Street, 7th Floor
Charlestown, MA 02129
Lee Zou, PhD
Massachusetts General Hospital Cancer Center
Harvard Medical School
James & Patricia Poitras Endowed Chair for Cancer Research
- Center for Cancer Research
- Massachusetts General Hospital Pathology Service
Explore the Zou Lab
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 DNA damage 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 understanding the molecular mechanisms by which different types of oncogenic events give rise to replication stress and genomic instability. Furthermore, we are developing new strategies to exploit the genomic instability and checkpoint addiction of different cancer cells in targeted cancer therapy.
Sensing of DNA Damage, Replication Stress, and Genomic Instability
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. We are especially interested in the mechanisms by which ATR is activated by replication stress and its functions in the replication stress response. Our recent studies have revealed that ATR plays an important role in the cellular responses to R loops, which arise from stable DNA:RNA hybrids during transcription. We found that ATR is activated by the collisions between replication forks and R loops, and it suppresses R loop-induced genomic instability through multiple mechanisms. We are extending our investigation to elucidate how ATR protects replication forks at R-loops and how ATR stabilizes the genome in response to aberrant R-loops.
Functions of ATR in regulating 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. Recently, 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). We have also developed new assays to understand how the alternative lengthening of telomere (ALT) pathway, which is regulated by ATR, is activated at telomeres. These new assays have helped us establish the framework of the ALT pathway for the first time, and uncovered the key mechanisms by which the ALT pathway is temporarily and spatially regulated during the cell cycle.
Functions of transcription and RNA in DNA repair
We are interested in the impacts of RNAs, including coding and non-coding RNAs, on genomic integrity. We recently discovered that RNA transcripts stimulate homologous recombination by forming a novel intermediate that contains both DNA:DNA and RNA:DNA hybrids. This intermediate, which we dubbed DR-loop, enhances the function of RAD51 in donor DNA. Our results demonstrate for the first time that RNA transcripts directly participate in DNA recombination, opening a new avenue to study the roles of RNA in DNA repair. These new findings will significantly change the current view of the functions of RNAs in DNA repair, providing new opportunities for cancer therapy.
Cancer Genomics, Tumor evolution and Targeted Cancer Therapy
During the evolution of tumors, cancer cells acquire mutations through a variety of mechanisms. We recently discovered that APOBEC3A/B proteins, two cytidine deaminases that are aberrantly expressed in multiple types of cancers, induce DNA replication stress and render cancer cells susceptible to ATR inhibition. Working with the team of Dr. Michael Lawrence, we find that APOBEC3A prefers substrate sites in DNA hairpins, leading to the discovery of passenger hotspot mutations in cancer. Furthermore, we find that the splicing factor mutations associated with 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 possibly other malignancies associated with RNA splicing defects.
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.
To apply, please send a CV with past research experience and contact information of three references to:
Lee Zou, PhD
Genois MM, Gagné JP, Yasuhara T, Jackson J, Saxena S, Langelier MF, AhI, Bedford MT, Pascal JM, Vindigni A, Poirier GG, Zou L. CARM1 regulates replication fork speed and stress response by stimulating PARP1. Mol Cell. 2021 Feb 18;81(4):784-800.e8.
Zhang JM, Genois MM, Ouyang J, Lan L, Zou L. Alternative lengthening of telomeres is a self-perpetuating process in ALT-associated PML bodies. Mol Cell. 2021 Mar 4;81(5):1027-1042.e4.
Ouyang J, Yadav T, Zhang JM, Yang H, Rheinbay E, Guo H, Haber DA, Lan L, Zou L. RNA transcripts stimulate homologous recombination by forming DR-loops. Nature. 2021 Jun;594(7862):283-288.
Simoneau A, Xiong R, Zou L. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells. Genes Dev. 2021 Sep 1;35(17-18):1271-1289.
Buisson R, Langenbucher A, Bowen D, Kwan EE, Benes CH, Zou L, and Lawrence SM. Passenger Hotspot Mutations in Cancer Driven by APOBEC3A and Mesoscale Genomic Features. Science 2019 Jun 28;364(6447):eaaw2872.
Kabeche, L., Nguyen, H. D., Buisson, R., and Zou, L. A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation. Science 2018, 359:108-114.
Research Image - Telomeric bridges in an ALT+ cancer cell lacking the BLM helicase.
Alternative lengthening of telomere (ALT) is a recombination-based mechanism to extend telomeres in cancer cells. We find that the BLM helicase is critical for resolving telomere recombination intermediates in ALT+ cancer cells. In the absence of BLM, unresolved recombination intermediates at telomeres result in chromosomal bridges in mitosis. Green: telomeres; Red: the telomere-binding protein TRF1; Blue: DNA.
Lee Zou, PhDPrincipal Investigator
- Elena Bittman
- Brian Brannigan
- Jessica Hopkins, PhD
- Rosaline Yuan-Chieh Hsu, PhD
- Ajinkya Kawale, PhD
- Wendy Leung, PhD
- Awura Ama Achiaa
- Jian Ouyang, PhD
- Parasvi Patel, PhD
- Sneha Saxena, PhD
- Mingchao Wang, PhD
- Nicholas Xanthopoulos
- Tribhuwan Yadav, PhD
- Haoran Yu
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- Jul | 1 | 2020
Lee Zou, PhD and Raul Mostoslavsky, MD, PhD Named Scientific co-Directors of the Mass General Cancer Center and Center for Cancer Research
Congratulations to Lee Zou, PhD and Raul Mostoslavsky, MD, PhD who will serve as Scientific co-Directors of the Mass General Cancer Center and Center for Cancer Research.