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A-Lien  Lu-Chang

A-Lien Lu-Chang Ph.D.

Academic Title: Professor
Primary Appointment: Biochemistry and Molecular Biology
Location: Biomedical Research Facility, Room 337
Phone: 410-706-4356
Fax: 410-706-1787
Lab: 410-706-4355

Personal History:

Dr. Lu-Chang received her Bachelor and Master degrees from National Taiwan University and Ph. D. from the University of North Carolina – Chapel Hill. She then completed her post-doctoral work at Duke University in the Department of Biochemistry. In 1984, she joined the faculty of the University of Maryland Medical School as an assistant professor of Biochemistry & Molecular Biology. She was subsequently promoted to associate professor with tenure in 1990 and professor in 1997. Dr. Lu-Chang became a member of the Program in Oncology, University of Maryland Greenebaum Cancer Center in 1994. She holds one patent from the United States Patent Office, and has been continuously funded as a principal investigator since 1985.

Research Interests:

Dr. Lu-Chang is a member of the Molecular and Structural Biology Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center Program in Oncology. As such, she collaborates with both basic and clinical research investigators to identify candidate proteins that may serve as markers for malignancy and/or targets for new drugs. Dr. Lu-Chang’s research centers on the DNA repair, DNA damage response, and cancer biology. She has been studying DNA repair for over 30 years.

Her lab is studying the interplays among DNA repair, DNA replication, cell cycle checkpoint, transcription, and chromatin remodeling. She has discovered the MutY base excision repair (BER) pathway in E. coli, fission yeast S. pombe, and mammalian cells. Her laboratory has shown that MutY glycosylase homolog (MYH) interacts with DNA replication enzymes (PCNA and RPA), mismatch repair enzymes (MSH2/MSH6), cell cycle checkpoint proteins (Rad9/Rad1/Hus1, the 9-1-1 complex) and an aging regulator (SIRT6).

Figure 1
figure 1

They have proposed that 9-1-1 serves as a platform to regulate BER repair (Fig. 1). These proteins are encoded by "care keeper" genes which maintain genomic stability. It has been shown that germline mutations in human MYH gene can lead to colorectal adenomatous polyposis (MYH-associated polyposis, MAP) while mutations in mismatch repair genes are associated with hereditary nonpolyposis colon cancer (HNPCC). Moreover, thymine DNA glycosylase(TDG), AP endonuclease (APE1), and 9-1-1 are essential for embryonic development.

Research Group

  • Bor-Jang Hwang, PhD, Post-doctoral Associate
  • in Jin, Research Technician

Lab Techniques and Equipment:

Laboratory Approaches

The Lu-Chang laboratory uses biochemistry, enzymology, cell culture, cell biology, molecular biology, chip array, and mouse models to study DNA repair, DNA damage response, and cancer biology. This includes molecular cloning and expression of proteins, protein-protein interactions, protein-DNA interactions, ChIP, cellular transfection with cDNAs and infection with lentivirus, cell and tissue culture, cell survival assay, and confocal laser scanning.

Research Projects:

1. MYH repair is coupled with DNA replication and cooperated with mismatch repair.

Dr. Lu-Chang’s group has shown that MYH repair is coupled with DNA replication and cooperated with mismatch repair.She collaborates with Dr. Gerald Wilson to analyze protein binding to DNA in solution using fluorescent anisotropy. They have shown that MYH interacts with APE endonuclease, proliferating cell nuclear antigen (PCNA), replication protein A (RPA), and MSH2/MSH6 mismatch repair enzyme. These protein-protein interactions ensure that MYH repair targets to daughter DNA strands but not parental DNA strands and that MYH repair is coordinated with other DNA metabolism. Because AP sites generated by MYH are mutagenic and cytotoxic, it is critical that they are properly transferred to and processed by APE1 (the 2nd enzyme of BER). The interaction between MYH and APE1 reduces the formation of AP site and DNA strand breaks. This has high impact to cancer initiation and cancer treatments. As enhanced DNA glycosylase activity and reduced APE1 activity will induce apoptosis. Thus, APE1 is an emerging anti-cancer drug target.

2. MYH repair is coordinated with cell cycle checkpoints.

Dr. Lu-Chang’s group has shown that the 9-1-1 complex interacts and stimulates several DNA glycosylases (MYH, OGG1, TDG, and NEIL1) and mismatch repair enzymes. Importantly, the interrupting SpMyh1 and SpHus1 interaction by a polypeptide confers a mutator phenotype and increases cell sensitivity to H2O2. Thus, preserving the MYH/9-1-1 interaction contributes significantly to increase genomic stability. Anti-cancer drugs can be developed to interrupt these protein-protein interactions. They have shown that the structural asymmetry of the heterotrimeric 9-1-1 complex correlates with an asymmetry in protein-protein interactions and DNA binding. Because 9-1-1 interacts with and stimulates nearly every enzyme in BER, they hypothesize that 9-1-1 provides a platform to coordinate BER. Our results support that MYH is an adaptor to recruit 9-1-1 to the damage site. The coordination of BER with cell cycle checkpoints is important for genomic stability and telomere maintenance.

3. MYH protects cells from oxidative DNA damage and carcinogenesis.

Dr. Lu-Chang’s group has characterized three hMYH mutants associated with MAP. These data define the pathogenic mechanisms underlying these hMYH polyposis-associated mutations and support the role of the hMYH pathway in carcinogenesis. They also show that MYH protects cells from oxidative DNA damage. MYH knockdown (KD) HeLa cells are more sensitive to H2O2 and contain higher 8-oxoG levels than non-target (NT) control cells. In addition, hMYH KD cells have altered DNA damage response (DDR) and cell cycle progression in response to oxidative stress. Thus, MYH is a vital DNA repair enzyme that protects cells from oxidative DNA damage and is critical for proper cellular DDR. These functional roles of MYH can explain why mutations in hMYH gene are prone for colon cancer and may be a biomarker for cancer treatment. Dr. Lu-Chang’s group has collaborated with Dr. Eric Toth to solve the first X-ray structure of hMYH. A crystal structure of a hMYH domain reveals that the flexible interdomain connector region projects away from the catalytic domain and can adopt a stabilized conformation to form a docking scaffold for partner proteins (APE1, Hus1, and SIRT6). Characterization of biological impact of MAP mutations within this region of hMYH will reveal whether these protein-protein interactions are important for genome maintenance.

4. MYH, APE1, 9-1-1, and SIRT6 are important for telomere integrity.

Dr. Lu-Chang also collaborates with Drs. Michal Zalzman (UMB) and Li Lan (University of Pittsburgh) to study the mechanisms linking oxidative stress to telomere shortening. They have applied immunostaining along with telomere fluorescence in situ hybridization (T-FISH) and a novel killer-red (KR) systems to show that hMYH is recruited to oxidatively damaged sites located within active chromatin and telomeres, but not within condensed chromatin in human cells. This property is unique to MYH because other DNA glycosylases such as Nth1, NEIL1, NEIL2, and MBD4 are recruited to both euchromatin and heterochromatin.

Figure 2
figure 2

5. TDG and SIRT1 are anti-cancer targets.

In another project, Dr. Lu-Chang’s group collaborates with Dr. Alex Drohat (UMB) on the studies of TDG. Recent reports indicate that TDG plays a critical role in DNA demethylation. They have shown that TDG interacts with the 9-1-1 complex and SIRT1 histone deacetylase. SIRT1 deacetylates TDG and suppresses TDG expression, to modulate TDG activity and alter its substrate preferences. Dr. Lu-Chang’s group has demonstrated that coexpression of TDG with estrogen receptor (ER¿) [with collaboration with Dr. Angela Brodie (UMB)] and sirt1 knockout cells are sensitive to 5-fluorouracil (FU) and methylation agents. They also showed that inhibitors of SIRT1 can reduce the cytotoxicity of two anti-cancer drugs: 5-fluorouracil (FU) and temozolomide (TMZ, a DNA methylating agent) in cancer chemotherapy (Fig. 2). They propose a model that TDG mediates SIRT1-dependent drug cytotoxicity. Thus, TDG and SIRT1 are potential biomarkers and therapeutic targets for cancer. With collaborations with Drs. Thomas Hornyak (UMB) and David Kaetzel (UMB), she plans to test SIRT1 inhibitors in melanoma therapy. The hope is that the insight gained from their studies will ultimately lead to the development of new therapeutic agents for cancer patients.

6. Study the effect of histone deacetylation and DNA demethylation on somatic reprogramming

Histone modification and DNA methylation control epigenetic gene expression and are key factors in somatic cell reprogramming toward pluripotency and differentiation. It has been shown that somatic cell reprogramming can be achieved by only OCT4 transcription factor (one of the master pluripotency genes) alone and small molecules. Dr. Lu-Chang’s group is investigating the effects of two key epigenetic modulators (SIRT1 and TDG) on improving the generation of induced pluripotent stem cells (iPSCs). They hypothesize that the expression of SIRT1 and TDG or employing their small molecule modulators will enhance reprogramming without the need for the delivery of ectopic OCT4. These studies will advance our understanding of the mechanism of reprogramming, and will take us a step closer towards advancing iPSCs technology from bench to bedside.


  1. Hwang, B. J., A. Madabushi, J. Jin, S.-Y. S. Lin, and A.-L. Lu. (2014). Histone/protein deacetylase SIRT1 is an aiticancer therapeutic target. Amer. J. Cancer Res. 4, 211-221. [PMID:24959376]
  2. Hwang, B. J., G. Shi, and A. L. Lu. (2014). Mammalian MutY homolog (MYH or MUTYH) protects cells from oxidative DNA damage. DNA Repair 13:10-21. [PMID: 24315136]
  3. Jin, J., B. J. Hwang, P. W. Chang, E. A. Toth, and A. L. Lu. (2014). Interaction of apurinic/apyrimidinic endonuclease 2 (Apn2) with Myh1 DNA glycosylase in fission yeast. DNA Repair 15:1-10. [PMID: 24559510]
  4. Luncsford, P. J., B. A. Manvilla, D. N. Patterson, S. S. Malik, J. Jin, B. J. Hwang, R. Gunther, S. Kalvakolanu, L. J. Lipinski, W. Yuan, W. Lu, A. C. Drohat, A.-L. Lu, and E. A. Toth. (2013). Coordination of MYH DNA glycosylase and APE1 endonuclease activities via physical interactions. DNA Repair 12:1043-1052. [PMID: 24209961]
  5. Madabushi, A., B. J. Hwang, J. Jin, and A. L. Lu. (2013). Histone deacetylase SIRT1 modulates and deacetylates DNA base excision repair enzyme thymine DNA glycosylase. Biochem. J. 456:89-98. [PMID: 23952905]
  6. Shi, G., D.-Y. Chang, C. C. Cheng, X. Guan, C. Venclovas and A-L. Lu (2006). Physical and functional interactions between MutY glycosylase homologue (MYH) and checkpoint proteins Rad9-Rad1-Hus1. Biochem J. 400: 53-62. [PMID:16879101]
  7. Guan, X., A. Madabushi, D.-Y. Chang, M. E. Fitzgerald, G. Shi, A. C. Drohat, and A-L. Lu (2007). The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates DNA repair enzyme TDG glycosylase. Nucleic Acids Res. 35, 6207-6218. [PMID:17855402]
  8. Guan, X., H. Bai, G. Shi, C. A. Theriot, T. K. Hazra, S. Mitra, and A-L. Lu (2007). The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates NEIL1 glycosylase. Nucleic Acids Res., 35, 2463-2472. [PMID:17395641]
  9. Bai, H., A. Madabushi, X. Guan, and Lu, A-L. (2010). Interaction between human mismatch repair recognition proteins and checkpoint sensor Rad9-Rad1-Hus1. DNA Repair, 9, 478-487. [PMID:20188637]
  10. Bai, H., S. Grist, G. Suthers, T. M. Wilson and A-L. Lu (2006). Functional characterization of human MutY homolog (hMYH) missense mutation (R231L) that is linked with hMYH-associated polyposis. Cancer Lett. 250, 74-81. [PMID:17081686]

Complete List of Published Work in MyBibliography