Zihua Gong, M.D., Ph.D.
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Phone: (216) 445-9652
Our laboratory is interested in understanding the molecular mechanisms underlying DNA repair pathway choice. BRCA1 and BRCA2 mutations are prevalent in familial breast and ovarian cancers. Cells with BRCA1 and BRCA2 mutations are exquisitely sensitive to PARP inhibitors (PARPi). However, treatment of BRCA mutant cancers with PARPi is not curative, and resistance to therapy is a major clinical problem. Our study investigates the mechanism on the competition and coordination of different DNA repair pathways, and uncovers key components in these pathways that we can explore to improve cancer therapy and overcome therapeutic resistance.
In other words…
Genomic instability caused by impaired DNA damage response and/or DNA repair is a triple-edged sword. On one hand, it is a driving force for tumorigenesis. On the other hand, defective DNA damage repair renders tumor cells more sensitive to DNA damaging agents, and thus allows for the use of radiation and many chemotherapeutic agents that induce DNA damage in clinic for cancer treatment. We are working on better understand the underlying mechanism on regulation of DNA repair pathway choice and resistance to PARP inhibition in BRCA1 mutant cancers, which are critical to develop new therapeutic strategies for cancer patients.
- Feng H, Lu J, Song X, Thongkum A, Zhang F, Lou L, Reizes O, Almasan A, Gong Z*. CK2 kinase-mediated PHF8 phosphorylation controls TopBP1 stability to regulate DNA replication. Nucleic Acids Res. 2020 Nov 4;48(19):10940-10952 gkaa756. Online ahead of print. PMID: 33010150
- Zhang F, Lou L, Peng B, Song X, Reizes O, Almasan A, Gong Z*. Nudix hydrolase NUDT16 regulates 53BP1 protein by reversing 53BP1 ADP-ribosylation. Cancer Res. 2020; 80(5):999-1010. PMID: 31911551
- Dai Y, Zhang F, Wang L, Shan S, Gong Z*, Zhou Z*. Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair. J Biol Chem. 2020 Jan 3;295(1):250-262. (* co-corresponding author) PMID: 31796627
- Sharma A, Alswillah T, Kapoor I, Debjani P, Willard B, Summers MK, Gong Z, Almasan A.USP14 is a deubiquitinase for Ku70 and critical determinant of non-homologous end joining repair in autophagy and PTEN-deficient cells. Nucleic Acids Res. 2020;48(2):736-747. PMID: 31740976
- Dai Y, Zhang A, Shan S, Gong Z*, Zhou, Z*. Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR. Nature Communications. 2018 May 29; 9: 2123 (* co-corresponding author) PMID: 29844495
- Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, Sirohi K, Li X, Wei Y, Lee H, Zhuang L, Chen G, Xiao ZD, Hung MC, Chen J, Huang P, Li W, Gan B. BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. 2018 Oct; 20(10):1181-1192. PMID: 30202049
- Hu Y, Lin J, Fang H, Fang J, Li C, Chen W, Liu S, Ondrejka S, Gong Z, Reu F, Maciejewski J, Yi Q, Zhao JJ. Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia. 2018 Oct; 32(10):2250-2262. PMID: 29632340
- Zhang A, Peng B, Huang P, Chen J*, Gong Z*. The p53-binding Protein 1-Tudor Interacting Repair Regulator Complex Participates in the DNA Damage Response. J Biol Chem. 2017, 292(16): 6461–6467. PMID: 28213517. This paper is selected as “Editor Picks”, only top 2 percent of manuscripts is selected in a year.
- Chen Z, MyTran K, Tang MF, Wang W, Gong Z*, Chen J*. Proteomic Analysis Reveals a Novel MutS Partner Involved in Mismatch Repair Pathway. Molecular & Cellular Proteomics 2016, 15(4):1299-308. PMID: 27037360. (* co-corresponding author)
- Wang J, Aroumougame A, Lobrich M, Li Y, Chen J*, Gong Z*. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev 2014, 28 (24): 2693-8. PMID: 25512557.
- Xu S1, Li X1, Gong Z1, Wang W, Li Y, Nair BC, Piao H, Yang K, Wu G, Chen J. Proteomic analysis of the human CDK family reveals a novel CDK5 complex involved in cell growth and migration. Molecular & Cellular Proteomics 2014, 13(11):2986-3000. PMID: 25096995. (1 these authors contributed equally to this work)
- Wang J, Chen J*, Gong Z*. TopBP1 controls BLM protein level to maintain genome stability. Mol Cell. 2013 Dec 12;52(5):667-78. PMID: 24239288
- Leung CC, Sun L, Gong Z, Burkat M, Edwards R, Assmus M, Chen J, Glover JN. Structural insights into recognition of MDC1 by TopBP1 in DNA replication checkpoint control. Structure. 2013 Aug 6;21(8):1450-9. PMID: 23891287
- Wang J, Leung JW, Gong Z, Feng L, Shi X, Chen J. PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis. J Biol Chem 2013, 288(5):3174-83. PMC3561539
- Wang J1, Gong Z1, Chen J. MDC1 collaborates with TopBP1 in DNA replication checkpoint control. J Cell Biol 2011, 193(2):267-73. (1 these authors contributed equally to this work). PMCID: PMC3080258.
- Gong Z, Chen J. E3 ligase RFWD3 participates in replication checkpoint control. J Biol Chem 2011, 286(25):2230
- Leung CC, Gong Z, Chen J, Glover JN. Molecular basis of BACH1/FANCJ recognition by TopBP1 in DNA replication checkpoint control. J Biol Chem 2011, 286(6):4292-301. PMCID: PMC3039391.
- Geunyeong P, Gong Z, Chen J, Kim JE. Characterization of the DOT1L network: Implications of diverse roles for DOT1L. Protein Journal 2010, 29(3): 213-223. PMID: 20431927
- Gong Z, Kim, JE, Leung, CC, Glover, JM, Chen J. BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol Cell 2010, 37(3):438-46. PMID: 20159562.
- Huang J1, Gong Z1, Ghosal G, Chen J. SOSS cooperates with RPA to maintain genomic stability. Mol Cell 2009, 35(3):384-93. (1 these authors contributed equally to this work). PMCID: PMC2756616.
- Gong Z, Cho YW, Kim JE, Ge K, Chen J. Accumulation of Pax2 Transactivation Domain Interaction Protein (PTIP) at Sites of DNA Breaks via RNF8-dependent Pathway Is Required for Cell Survival after DNA Damage. J Biol Chem 2009, 284(11):7284-93. PMCID: PMC2652327
Zihua Gong, MD, PhD, was recently awarded a new grant from the National Cancer Institute, part of the National Institutes of Health, to continue his research related to BRCA1- and BRCA2-associated breast and ovarian cancer.