Junran Zhang, MD, PhD
Assistant Professor of Radiation Oncology (Tenure Track)email@example.com 216.368.1140 (o) 216.368.1142 (f)
DNA double strand breaks (DSBs) are the most dangerous type of DNA lesion, because incorrectly repaired DSB can result in genomic instability, a major driving force in the onset and development of cancer. Cells that are deficient in DNA DSB repair are sensitive to ionizing radiation (IR) and chemotherapeutic drugs that cause DNA DSBs. Therefore, perturbations of DSB repair that promote carcinogenesis by causing genomic instability may also be the Achilles' heel of cancer. Understanding the molecular mechanisms that are involved in DNA DSB responses has become a central topic in cancer biology and radiation biology. The goal of my research is to identify the molecular mechanisms maintaining genomic stability and to explore novel strategies targeting cancer cells by studying responses to DNA DSB formation.
Three major ongoing research projects in my group:
- Delineate the role of RNF126 in DNA DSB response and its implications in cancer therapy.
- Determine the mechanisms controlling homologous recombination-mediated repair in response to replication stress, especially at Common Fragile Sites (CFSs). CFSs are the genomic regions prone to form breaks during replication stress and are frequent targets of genomic alterations in both tumors and precancerous lesions.
- Identify novel factors sensitizing cancer cells to ionizing radiation and to CHK1 inhibitors using Decode pooled lentiviral shRNA screening libraries.
Bibliography (Selected from 48 publications)
1. Zhang, Y., Lai, J., Du, Z., Gao, J., Yang, S., Gorityala, S., Xiong, X., Deng, O., Ma, Z., Yan, C., Susana, G., Xu, Y. and Zhang, J. (2016) Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress. Oncotarget.
2. Yang, H.Y., Barbi, J., Wu, C.Y., Zheng, Y., Vignali, P.D., Wu, X., Tao, J.H., Park, B.V., Bandara, S., Novack, L., Ni, X., Yang, X., Chang, K.Y., Wu, R.C., Zhang, J., Yang, C.W., Pardoll, D.M., Li, H. and Pan, F. (2016) MicroRNA-17 Modulates Regulatory T Cell Function by Targeting Co-regulators of the Foxp3 Transcription Factor. Immunity, 45, 83-93.
3. Wang, Y., Deng, O., Feng, Z., Du, Z., Xiong, X., Lai, J., Yang, X., Xu, M., Wang, H., Taylor, D., Yan, C., Chen, C., Difeo, A., Ma, Z. and Zhang, J. (2016) RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. Oncogene, 35, 1363-1372.
4. Hedrich, W.D., Xiao, J., Heyward, S., Zhang, Y., Zhang, J., Baer, M.R., Hassan, H.E. and Wang, H. (2016) Activation of the Constitutive Androstane Receptor Increases the Therapeutic Index of CHOP in Lymphoma Treatment. Molecular cancer therapeutics, 15, 392-401.
5. Graziano, S., Johnston, R., Deng, O., Zhang, J. and Gonzalo, S. (2016) Vitamin D/vitamin D receptor axis regulates DNA repair during oncogene-induced senescence. Oncogene.
6. Cui, H., Li, X., Han, C., Wang, Q.E., Wang, H., Ding, H.F., Zhang, J. and Yan, C. (2016) The Stress-responsive Gene ATF3 Mediates Dichotomous UV Responses by Regulating the Tip60 and p53 Proteins. The Journal of biological chemistry, 291, 10847-10857.
7. Xiong, X., Du, Z., Wang, Y., Feng, Z., Fan, P., Yan, C., Willers, H. and Zhang, J. (2015) 53BP1 promotes microhomology-mediated end-joining in G1-phase cells. Nucleic acids research, 43, 1659-1670.
8. Wang, Z., Xu, D., Ding, H.F., Kim, J., Zhang, J., Hai, T. and Yan, C. (2015) Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene, 34, 4975-4984.
9. Wang, Z., Kim, J., Teng, Y., Ding, H.F., Zhang, J., Hai, T., Cowell, J.K. and Yan, C. (2015) Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5CK8 epithelial cells. Oncogene.
10. Li, L., Li, H., Garzel, B., Yang, H., Sueyoshi, T., Li, Q., Shu, Y., Zhang, J., Hu, B., Heyward, S., Moeller, T., Xie, W., Negishi, M. and Wang, H. (2015) SLC13A5 is a novel transcriptional target of the pregnane X receptor and sensitizes drug-induced steatosis in human liver. Molecular pharmacology, 87, 674-682.
11. Krishnamurthy, N., Liu, L., Xiong, X., Zhang, J. and Montano, M.M. (2015) Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells. Cancer biology & therapy, 16, 518-527.
12. Kan, C. and Zhang, J. (2015) BRCA1 Mutation: A Predictive Marker for Radiation Therapy? International journal of radiation oncology, biology, physics, 93, 281-293. ASTRO issued a press release to highlight this manuscript to the national media
13. Cui, H., Guo, M., Xu, D., Ding, Z.C., Zhou, G., Ding, H.F., Zhang, J., Tang, Y. and Yan, C. (2015) The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nature communications, 6, 6752.
14. Chatterjee, P., Choudhary, G.S., Alswillah, T., Xiong, X., Heston, W.D., Magi-Galluzzi, C., Zhang, J., Klein, E.A. and Almasan, A. (2015) The TMPRSS2-ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition. Molecular cancer therapeutics, 14, 1896-1906.
15. Brett-Morris, A., Wright, B.M., Seo, Y., Pasupuleti, V., Zhang, J., Lu, J., Spina, R., Bar, E.E., Gujrati, M., Schur, R., Lu, Z.R. and Welford, S.M. (2014) The polyamine catabolic enzyme SAT1 modulates tumorigenesis and radiation response in GBM. Cancer research, 74, 6925-6934.
16. Zhang, J. (2013) The role of BRCA1 in homologous recombination repair in response to replication stress: significance in tumorigenesis and cancer therapy. Cell & bioscience, 3, 11. Most highly accessed article from that journal since its publication.
17. Li, Y., Chen, X., Wang, Z., Zhao, D., Chen, H., Chen, W., Zhou, Z., Zhang, J., Li, H. and Chen, C. (2013) The HECTD3 E3 ubiquitin ligase suppresses cisplatin-induced apoptosis via stabilizing MALT1. Neoplasia, 15, 39-48.
18. Grotsky, D.A., Gonzalez-Suarez, I., Novell, A., Neumann, M.A., Yaddanapudi, S.C., Croke, M., Martinez-Alonso, M., Redwood, A.B., Ortega-Martinez, S., Feng, Z., Lerma, E., Ramon y Cajal, T., Zhang, J., Matias-Guiu, X., Dusso, A. and Gonzalo, S. (2013) BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells. The Journal of cell biology, 200, 187-202.
19. Feng, Z. and Zhang, J. (2012) A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest. Nucleic acids research, 40, 726-738.
20. Redwood, A.B., Perkins, S.M., Vanderwaal, R.P., Feng, Z., Biehl, K.J., Gonzalez-Suarez, I., Morgado-Palacin, L., Shi, W., Sage, J., Roti-Roti, J.L., Stewart, C.L., Zhang, J. and Gonzalo, S. (2011) A dual role for A-type lamins in DNA double-strand break repair. Cell Cycle, 10, 2549-2560.
21. Helmink, B.A., Tubbs, A.T., Dorsett, Y., Bednarski, J.J., Walker, L.M., Feng, Z., Sharma, G.G., McKinnon, P.J., Zhang, J., Bassing, C.H. and Sleckman, B.P. (2011) H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature, 469, 245-249.
22. Chen, H., Ma, Z., Vanderwaal, R.P., Feng, Z., Gonzalez-Suarez, I., Wang, S., Roti Roti, J.L. and Gonzalo, S and Zhang, J., (2011) The mTOR inhibitor rapamycin suppresses DNA double-strand break repair. Radiation research, 175, 214-224.
23. Shi, W., Feng, Z., Gonzalez-Suarez, I., Vanderwaal, R.P., Wu, X., Powell, S.N., Roti Roti, J.L. and Gonzalo, S and Zhang, J., (2010) The role of RPA2 phosphorylation in homologous recombination in response to replication arrest. Carcinogenesis, 31, 994-1002.
24. Shi, W., Ma, Z., Willers, H., Akhtar, K., Scott, S.P., Powell, S and Zhang, J. (2008) Disassembly of MDC1 foci is controlled by ubiquitin-proteasome-dependent degradation. The Journal of biological chemistry, 283, 31608-31616.
25. Treszezamsky, A.D., Kachnic, L.A., Feng, Z., Zhang, J., Tokadjian, C. and Powell, S.N. (2007) BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. Cancer research, 67, 7078-7081.
26. Zhuang, J., Zhang, J., Willers, H., Wang, H., Chung, J.H., van Gent, D.C., Hallahan, D.E., Powell, S.N. and Xia, F. (2006) Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining. Cancer research, 66, 1401-1408. (The first two authors contributed equally to this work).
27. Pandita, R.K., Sharma, G.G., Laszlo, A., Hopkins, K.M., Davey, S., Chakhparonian, M., Gupta, A., Wellinger, R.J., Zhang, J., Powell, S.N., Roti Roti, J.L., Lieberman, H.B. and Pandita, T.K. (2006) Mammalian Rad9 plays a role in telomere stability, S- and G2-phase-specific cell survival, and homologous recombinational repair. Molecular and cellular biology, 26, 1850-1864.
28. Ma, Z., Gibson, S.L., Byrne, M.A., Zhang, J., White, M.F. and Shaw, L.M. (2006) Suppression of insulin receptor substrate 1 (IRS-1) promotes mammary tumor metastasis. Molecular and cellular biology, 26, 9338-9351.
29. Zhang, J. and Powell, S.N. (2005) The role of the BRCA1 tumor suppressor in DNA double-strand break repair. Molecular cancer research : MCR, 3, 531-539.
30. Zhang, J., Ma, Z., Treszezamsky, A. and Powell, S.N. (2005) MDC1 interacts with Rad51 and facilitates homologous recombination. Nature structural & molecular biology, 12, 902-909.
31. Litman, R., Peng, M., Jin, Z., Zhang, F., Zhang, J., Powell, S., Andreassen, P.R. and Cantor, S.B. (2005) BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer cell, 8, 255-265.
32. Zhang, J., Willers, H., Feng, Z., Ghosh, J.C., Kim, S., Weaver, D.T., Chung, J.H., Powell, S.N. and Xia, F. (2004) Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Molecular and cellular biology, 24, 708-718.
33. Feng, Z., Kachnic, L., Zhang, J., Powell, S.N. and Xia, F. (2004) DNA damage induces p53-dependent BRCA1 nuclear export. The Journal of biological chemistry, 279, 28574-28584.
34. Ma, Z.F., Wang, Z.Y., Zhang, J.R., Gong, P. and Chen, H.L. (2001) Carcinogenic potential of duodenal reflux juice from patients with long-standing postgastrectomy. World journal of gastroenterology, 7, 376-380.