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Yue Zou, Ph.D.
Research in my laboratory focuses on understanding the molecular mechanisms of genome instability and DNA damage responses (DDR) such as DNA repair, DNA damage checkpoint signaling, and cell death, as well as coordination among these pathways. One of the greatest challenges to the human health is the voluntary and involuntary exposures to a variety of exogenous genotoxic agents (typically UV irradiation and environmental carcinogens), which may cause DNA damage, mutations, and thus genome instability. Such instability is the major cause of human cancer. As a cellular defense system against DNA damage to maintain the integrity of genetic materials, DNA repair recognizes and removes DNA lesions, while activation of DNA damage checkpoints leads to the arrest of cell cycle progression, allowing sufficient time for DNA repair to remove the damage before the damage could cause permanent changes in the genome. We are particularly interested in ATR (ataxia telangiectasia and Rad3-related)-dependent DNA damage checkpoint signaling or replication checkpoint control, and its regulation of DNA repair as well as its role in cell death. ATR is a protein kinase of the phosphoinositide 3-kinase-related protein kinases (PIKK) family member and a sensor for replication stresses, typically caused by DNA damage. Major substrates of ATR include p53, Chk1 and many other downstream proteins. Although ATR has been extensively studied, its prolyl isomerization and related functions remain unknown. We recently reported that ATR has a novel activity at mitochondria to suppress the DNA damage-induced apoptosis. Remarkably, ATR is prolyl isomerically modified in DDR and adopts different isomeric forms (cis- and trans-isomers) for its mitochondrial activity and nuclear checkpoint activity, respectively. Its mitochondrial activity is regulated by prolyl isomerase Pin1 and is independent of ATR’s hallmark nuclear checkpoint kinase activity and ATRIP. Also interestingly, ATR contains a BH3-like domain that allows it to act like a Bcl-2 family proteins. Given that ATR has been a popular target for cancer therapy, the long-term goal of our studies is to provide new mechanistic insights for developing better strategies for cancer therapy.
Another major effort in my lab is to determine the molecular basis of accumulation of DNA damage, particularly DNA double-strand breaks (DSBs) in laminopathy-based premature aging and normal aging. Patients who have the rare disease Hutchinson-Gilford progeria syndrome (HGPS) suffer from premature aging. HGPS is attributed to the deficiency in maturation of lamin A protein, a major inner component of the nuclear envelope and skeleton. We and others reported that the accelerated aging phenotypes appear to result from genomic instability induced by DSB accumulation, an observation similar to that in normal aging. However, how these DSBs are produced as the result of the lamin A deficiency and why they are resistant to repair and thus accumulate remain unknown. Our investigation is to delineate the underlying mechanism and the potential implication in normal aging. Such understanding may provide new therapeutic strategies for treatment of the devastating disease.
2. Wu X, Dong Z, Wang CJ, Barlow LJ, Fako V, Serrano MA, Zou Y, Liu JY, Zhang JT (2016) FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1. Proc Natl Acad Sci USA. pii: 201609934. [Epub ahead of print].
3. Hilton BA, Li Z, Musich PR, Wang H, Cartwright BM, Serrano M, Zhou XZ, Lu KP, and Zou Y (2015) ATR Plays a Direct Antiapoptotic Role at Mitochondria Which Is Regulated by Prolyl Isomerase Pin1. Molecular Cell, 60, 35-46. (Highlighted in Nature Review Mol. Cell Biol. 16, 640, 201532).
4. Jarrett SG, Horrell EM, Christian PA, Vanover JC, Boulanger MC, Zou Y, D'Orazio JA. (2014) PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage. Molecular Cell 54, 999-1011.
5. Serrano MA, Li Z, Dangeti M, Musich PR, Patrick S, Roginskaya M, Cartwright B, Zou Y (2013) DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair. Oncogene 32, 2452-2462.
6. Tang H, Hilton B, Musich PR, Fang DZ and Zou Y (2012) Replication Factor C1, the Large Subunit of Replication Factor C, Is Proteolytically Truncated in Hutchinson-Gilford Progeria Syndrome. Aging Cell 11, 363-365.
7. Li Z, Musich PR, Serrano MA, Dong Z and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR is p53-dependent and occurs primarily in S-phase. PLoS ONE 6, e28326
8. Shell SM, Li Z, Shkriabai N, Kvaratskhelia M, Brosey C, Serrano MA, Chazin WJ, Musich PR, and Zou Y (2009) Checkpoint Kinase ATR Promotes Nucleotide Excision Repair of UV-induced DNA Damage via Physical Interaction with XPA. J. Biol. Chem. 284, 24213-24222.
9. Liu Y, Wang Y, Rusinol AE, Sinensky MS, Liu J, Shell SM, and Zou Y (2008) Involvement of Xeroderma Pigmentosum Group A (XPA) in Progeria Arising from Defective Maturation of Prelamin A. FASEB J. 22, 603-611.
10. Wu X, Shell SM, and Zou Y (2007) ATR-Dependent Checkpoint Modulates XPA Nuclear Import in Response to UV Irradiation. Oncogene 26, 757-764.
11. Cai L, Roginskaya M, Qu Y, Yang Z, Xu Y, and Zou Y (2007) A Structural Characterization of Human RPA Sequential Binding to Single-Stranded DNA Using ssDNA as a Molecular Ruler. Biochemistry 46, 8226-8233.
12. Wu X, Shell SM, Yang Z, and Zou Y (2006) Phosphorylation of Nucleotide Excision Repair Factor XPA by ATR-Dependent Checkpoint Pathway Promotes Cell Survival in Response to UV Irradiation. Cancer Research 66:2997-3005.
13. Liu Y, Rusinol A, Sinensky M, Wang Y, and Zou Y (2006) DNA Damage Responses in Progeroid Syndromes Arising from Defective Maturation of Prelamin A. J. Cell Science 119, 4644-4649.
14. Liu Y, Kvaratskhelia M, Hess S, Qu Y, and Zou Y (2005) Modulation of Replication Protein A (RPA) Function by Its Hyperphosphorylation-Induced Subtle Conformational Change Involving DNA Binding Domain B. J. Biol. Chem. 32775-32783.
15. Shell SM, Hess S, Kvaratskhelia M, and Zou Y (2005) Mass Spectrometric Identification of Lysines Involved in the Interaction of Human Replication Protein A with ssDNA. Biochemistry 44, 971 -978.
16. Wu X, Shell SM, and Zou Y (2005) Interaction and co-localization of Rad9/Rad1/Hus1 checkpoint complex with Replication protein A in human cells. Oncogene 24, 4728-4735.
17. Minko IG, Zou Y, Lloyd RS (2002) Incision of DNA-protein crosslinks by UvrABC nuclease suggests a potential repair pathway involving nucleotide excision repair. Proc Natl Acad Sci USA 99, 1905-1909.
18. Yang GZ, Liu Y, Mao LY, Zhang J, Zou Y (2002) “Dimerization of Human XPA and Formation of XPA2-RPA Protein Complex” Biochemistry 41, 13012-13020.
19. Zou Y, Van Houten B (1999) Strand opening by the UvrA(2)B complex allows dynamic
recognition of DNA damage. The EMBO J. 18, 4889-4901.