Welcome to Yang lab. We utilize a combination of techniques including biochemistry, molecular and cellular biology, organic synthesis and mass spectrometry to study DNA-protein cross-link (DPC), a type of extremely cytotoxic and mutagenic DNA damage.
DPCs are induced by both endogenous sources and various physical and chemical agents including ionizing radiation, UV light, transition metal ions, environmental contaminants, and common anticancer drugs (e.g., nitrogen mustards and platinum compounds). Due to the bulky sizes, DPCs could block DNA replication and transcription. We aim to expand our fundamental knowledge on the biological effects and repair mechanisms of DPCs, which will help us understand the etiology of DPC induced diseases, such as cancers, and importantly assist us develop strategies to inhibit DPC repair for synergizing the current DPC inducing drugs in chemotherapy.
Our current research projects include:
- Chemical synthesis of biologically relevant DPCs.
- Understanding the biological effects of DPCs.
- Investigating the molecular mechanisms of DPC repair.
- Targeting DPC repair with small molecule inhibitors.
- Biochemical applications of DPCs.
We look for motivated postdoctoral fellows, graduate and undergraduate students with interests and expertise in biochemistry, molecular & cell biology, and organic synthesis. Please contact us at kun.yang@austin.utexas.edu or 512-471-4843 if you are interested in joining our research group.
Principal Investigator
Dr. Kun Yang is an assistant professor in Division of Chemical Biology and Medicinal Chemistry at College of Pharmacy, University of Texas at Austin. He obtained his B.S. in Biology from Sichuan University in 2010. In 2016, he received his Ph.D. in Biochemistry from University of Delaware under the supervision of Dr. Zhihao Zhuang. Thereafter, he joined Dr. Marc Greenberg’s group in the Department of Chemistry at Johns Hopkins University as a postdoctoral fellow. He started his independent research career at UT Austin in 2019. His research interest focuses on DNA damage & repair.
Postdoctoral Fellow
Dr. Zhishuo Wang, Ph.D. Sichuan University, China (Professor Jingsong You)
Graduate Student
Xiaoying Wei, B.S. UT Austin, Biochemistry
Cameron Bryan, B.S. UT Austin, Biochemistry
Ying Peng, M.S. University of Delaware, Food Chemistry
Undergraduate Student
Trisha Anand, Biochemistry, Class of 2022
Independent work at UT Austin (2019-present)
6. Bryan C, Le J, Wei X, Yang K. Saccharomyces cerevisiae apurinic/apyrimidinic endonuclease 1 repairs abasic site-mediated DNA-peptide/protein cross-links. (2023) DNA Repair. 126, 103501.
5. Wei X, Person M, Yang K. Tyrosyl-DNA phosphodiesterase 1 excises the 3′-DNA-ALKBH1 cross-link and its application for 3′-DNA-ALKBH1 cross-link characterization by LC-MS/MS. (2022) DNA Repair. 119, 103391.
4. Yang K, Wei X, Le J, Rodriguez N. Human TREX1 repairs 3′-end DNA lesions in vitro. (2022) Chem. Res. Toxicol. 35, 935-939.
3. Bryan C, Wei X, Wang Z, Yang K. In vitro eradication of abasic site-mediated DNA-peptide/protein cross-links by Escherichia coli long-patch base excision repair. (2022) J. Biol. Chem. 298, 102055.
2. Wei X, Wang Z, Hinson C, Yang K. Human TDP1, APE1, and TREX1 repair 3′-DNA-peptide/protein cross-links arising from abasic sites in vitro. (2022) Nucleic Acids Res. 50, 3638-3657.
1. Wei X, Bryan C, Peng Y, Yang K. Mechanisms of DNA−protein cross-link formation and repair. (2021) BBA-Proteins and Proteomics. 1869, 140669.
Postdoc work at Johns Hopkins Univ. (2016-2019) (* supervised undergraduate student)
10. Yang K, Sun H, Lowder L, Varadarajan S, Greenberg MM. Reactivity of N3-Methyl-2′-Deoxyadenosine in Nucleosome Core Particles. (2019) Chem. Res. Toxicol. 32: 2118-2124. ACS Editors’ Choice.
- N3-methyl-2′-deoxyadenosine (MdA) is the second major damaged product (10-20%) when DNA is exposed to methylating agents.
- Nucleosome core particles (NCPs) containing site-specific MdA were produced using a strategy in which the minor groove binding Me-Lex molecule serves as a sequence specific methylating agent.
- Hydrolysis of MdA to yield abasic site (AP) is inhibited in NCPs.
- DNA-protein cross-links (DPCs) are formed between histone proteins and MdA (minor product) as well as between histone proteins and AP (major product).
9. Yang K, Greenberg MM. DNA-Protein Cross-link Formation in Nucleosome Core Particles Treated with Methyl Methanesulfonate. (2019) Chem. Res. Toxicol. 32: 2144-2151.
8. Sun H, Zheng Li, Yang K, Greenberg MM. Positional Dependence of DNA Hole Transfer Efficiency in Nucleosome Core Particles. (2019) J. Am. Chem. Soc. 141: 10154-10158.
7. Yang K, Prasse C, Greenberg MM. Effect of Histone Lysine Methylation on DNA Lesion Reactivity in Nucleosome Core Particles. (2019) Chem. Res. Toxicol. 5: 910-916. (Invited article, Specific Issue-Epigenetics in Toxicology).
6. Byrne RS, Yang K, Rokita ES. Effect of Nucleosome Assembly on Alkylation by a Dynamic Electrophile. (2019) Chem. Res. Toxicol. 5: 917-925.
5. Rana A, Yang K, Greenberg MM. Reactivity of the Major C5′-Oxidative DNA Damage Product in Nucleosome Core Particles. (2019) ChemBioChem. 20: 672-676.
4. Yang K, Greenberg MM. Histone Tail Sequences Balance Their Role in Genetic Regulation and the Need to Protect DNA Against Destruction in Nucleosome Core Particles Containing Abasic Sites. (2019) ChemBioChem. 20: 78-82.
3. Yang K, Park D, Tretyakova NY, Greenberg MM. Histone Tails Decrease N7-Methyl-2′-Deoxyguanosine Depurination and Yield DNA-Protein Cross-links in Nucleosome Core Particles and Cells. (2018) Proc. Natl. Acad. Sci. USA. 115: E11212-E11220. Highlighted by C&EN news.
- N7-methyl-2′-deoxyguanosine (MdG) is the major damage product (60-80%) when DNA is treated by methylating agents.
- MdG is often NOT consider to be toxic or mutagenic.
- MdG slowly hydrolyzes to yield abasic site (AP) which is toxic and mutagenic.
- Nucleosomal DNA containing site-specific MdG was generated by polymerase incorporation of MdGTP followed by enzymatic ligation.
- MdG hydrolysis is inhibited by the proximal Lys and Arg residues within the histone tails.
- Reversible DNA-protein cross-links (DPCs) are formed between histone proteins and MdG, which were detected from NCPs containing site-specific MdG, as well as the methyl methanesulfonate treated mammalian cells.
- This is the first report that DPCs are induced by monofunctional alkylating agents.
2. Yang K, Greenberg MM. Enhanced Strand Scission at Abasic Sites within Clustered Lesions in NCPs. (2018) ChemBioChem. 19: 2061-2065.
1. Wang R*, Yang K, Banerjee S, Greenberg MM. Rotational Effects Within Nucleosome Core Particles on Abasic Site Reactivity. (2018) Biochemistry. 57: 3945-3952.
PhD work in Univ. of Delaware (2011-2016) (# equal contribution)
7. Gui W, Ott CA, Yang K, Chung J, Zhuang Z. Cell-Permeable Activity-based Ubiquitin Probes Enable Intracellular Profiling of Human Deubiquitinases. (2018) J. Am. Chem. Soc. 140: 12424-12433.
6. Gong P, Davidson G, Gui W, Yang K, Bozza WP, Zhuang Z. Activity-Based Ubiquitin-Protein Probes Reveal Target Protein Specificity of Deubiquitinating Enzymes. (2018) Chem. Sci. 9: 7859-7865.
5. Yang K#, Li G#, Gong P, Gui W, Yuan L, Zhuang Z. Chemical Protein Ubiquitylation with Preservation of the Native Cysteine Residues. (2016) ChemBioChem. 17: 995-998.
- A chemical strategy was developed for chemical protein ubiquitination through sequential Cys protection and deprotection.
4. Tsutakawa SE, Yan C, Xu X, Weinacht CP, Freudenthal BD, Yang K, Zhuang Z, Washington MT, Tainer JA, Ivanov I. Structurally Distinct Ubiquitin- and Sumo-Modified PCNA: Implications for Their Distinct Roles in the DNA Damage Response. (2015) Structure. 23: 724-733.
3. Yang K#, Gong P#, Gokhale P, Zhuang Z. Chemical Protein Polyubiquitination Reveals the Role of a Noncanonical Polyubiquitin Chain in DNA Damage Tolerance. (2014) ACS Chem. Biol. 9: 1685-1691.
- Site-specific and chain length controlled Lys63-linked polyUb-PCNA proteins were chemically generated.
- DNA replication and translesion DNA synthesis (TLS) were reconstituted with purified protein complexes.
- Lys63-linked polyUb-PCNA inhibits DNA replication and error-prone TLS.
2. Yang K#, Weinacht CP#, Zhuang Z. Regulatory Role of Ubiquitin in Eukaryotic DNA Translesion Synthesis. (2013) Biochemistry. 52: 3217-3224.
1. Bozza WP, Yang K, Wang J, Zhuang Z. Developing Peptide-based Multivalent Antagonists of Proliferating Cell Nuclear Antigen and a Fluorescence-based PCNA Binding Assay. (2012) Anal. Biochem. 427: 69-78.
