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A-Lien Lu-Chang, PhD

Academic Title:

Professor

Primary Appointment:

Biochemistry and Molecular Biology

Location:

Biomedical Research Facility, Room 339

Phone (Primary):

410-706-4356

Fax:

410-706-1787

Education and Training

Education

1971                B. S., Botany, National Taiwan University, Taiwan

1973                M. S., Plant Physiology, National Taiwan University, Taiwan

1980                Ph.D., Biochemistry, University of North Carolina at Chapel Hill.

 

Post Graduate Education

1980-1984              Postdoctoral Fellow

DukeUniversity

Durham, North Carolina

Biosketch

Ongoing Research Support

2014-MSCRFE-0656                                                                                      Lu-Chang (PI)                                                 07/01/2014–11/30/2016                                        

Maryland Stem Cell Research Fund                                                                                                                    *Currently No Cost Extension

The effects of histone deacetylation and DNA demethylation on somatic cell reprogramming

The goal of this project is to enhance the induction efficiency and quality of induced pluripotent stem cells (iPSCs) by altering epigenetic state of somatic cells through modulating the activities of several key epigenetic and DNA repair regulators including SIRT1 and TDG.

Role: PI

Completed Research Support in past 3 years

R01 CA078391-16                                                                                          Lu-Chang (PI)                                        09/01/2009-01/31/2015                      

Repair of Oxidatively Damaged Guanines

The major goal of this project is to study the interactions among DNA repair proteins, cell cycle checkpoint proteins, and histone deacetylases.

Role: PI

Pending Grant

R01 GM118837-01A1                                                                                    Lu-Chang (PI)                                        12/01/2016-11/30/2021

The role of the checkpoint clamp in DNA repair

The goal of this project is to define the biochemical and functional relationships between 9-1-1 and two enzymes (MYH and APE1) that mediate initial steps of BER.

Role: PI

(Received 9th percentile)

Research/Clinical Keywords

DNA repair, DNA damage response, protein-protein interaction, protein modification, cancer treatment

Highlighted Publications

  1. Chang, D.-Y. & Lu, A-L. Interaction of checkpoint proteins Hus1/Rad1/Rad9 with DNA base excision repair enzyme MutY homolog (MYH) in fission Yeast, Schizosaccharomyces pombe.J. Biol. Chem. 280: 408-417. 2004.
  2. Bai, H., Jones, S., Guan, X., Wilson, T. M., Sampson, J. R., Cheadle, J. P., & Lu, A-L. Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis.  Nucl. Acids. Res. 33: 597-604. 2005.
  3. Shi, G., Chang, D.-Y., Cheng, C. C., Guan, X., Venclovas, C. & Lu, A-L.  Physical and functional interactions between MutY glycosylase homoloque (MYH) and checkpoint proteins Rad9-Rad1-Hus1. Biochem J. 400: 53-62. 2006.

  4. Parker, A., Gu, Y. S., Mahoney, W., Lee, S. H., Singh, K. K., & Lu, A-L.  Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. J. Biol. Chem. 276: 5547-5555. 2001. 

  5. Luncsford, P. J.*, Chang, D. Y.*, Shi, G., Bernstein, J., Madabushi, A., Patterson, D. N., Lu, A-L.#, & Toth, E. A#. Structural hinge in eukaryotic MutY homologues mediates catalytic activity and Rad9-Rad1-Hus1 checkpoint complex interactions. J. Mol. Biol., 403; 351-70, 2010. [PMID:20816984] (*Equal contribution; #corresponding authors)
  6. Chang D.-Y., Shi G., Durand-Dubief M., Ekwall K., & Lu A-L. The role of MutY homolog (Myh1) in controlling the histone deacetylase Hst4 in the fission yeast Schizosaccharomyces pombe. J. Mol. Biol., 405: 653-665, 2011. [PMID: 21110984]
  7. Madabushi, A., Hwang, B.-J. Jin, J., & Lu A-L. Histone deacetylase SIRT1 modulates and deacetylates DNA base excision repair enzyme thymine DNA glycosylase. Biochem. J. 456; 89-98, 2013. [PMID: 23952905]
  8. Luncsford, P. J., Manvilla, B. A., Patterson, D. N., Malik, S. S., Jin, J., Hwang, B-J., Gunther, R., Kalvakolanu, S., Lipinski, L. J., Yuan, W., Lu W., Drohat, A. C., Lu, A-L., & Toth, E. A. Coordination of MYH DNA glycosylase and APE1 endonuclease activities via physical interactions DNA Repair. DNA Repair, 12; 1043-1052, 2013. [PMID: 24209961]
  9. Hwang, B.-J., Shi G., & Lu A-L. Mammalian MutY homolog (MYH or MUTYH) protects cells from oxidative DNA damage.  DNA Repair, 13; 10-21, 2014. [PMID: 24315136]
  10. Jin, J., Hwang, B.-J., Chang, P.-W., Toth, E. A., & Lu, A-L. Interaction of apurinic/apyrimidinic endonuclease 2 (Apn2) with Myh1 DNA glycosylase in fission yeast. DNA Repair, 15; 1-10, 2014. [PMID: 24559510]
  11. Hwang, B.-J., Madabushi, A., Jin, J., Lin, S.-Y. S., & Lu, A-L. Histone/protein deacetylase SIRT1 is an anticancer therapeutic target. Amer. J. Cancer Res. 4; 211-221, 2014. [PMID: 24959376]
  12. Lim, P. X., Patel, D. R., Poisson K. E., Basuita M., Tsai C., Lyndaker A. M., Hwang, B.-J., Lu, A-L., Weiss R. S. Genome Protection by the 9-1-1 complex subunit HUS1 requires clamp formation, DNA contacts, and ATR signaling-independent effector functions. J. Biol. Chem. 290;14826-40, 2015. [PM:25911100]
  13. Hwang, B.-J., Jin, J., Gao, Y., Shi, G., Madabushi, A., Yan, A., Guan, X., Zalzman, M. Nakajima, S., Lan, L., & Lu, A-L. SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclaes, and Rad9-Rad1-Hus1 checkpoint clamp. BMC. Mol. Biol.;12-. 2015. [PMCID: PMC4464616] [PMID: 26063178]
  14. Hwang, B. J., Jin, J., Gunther, R., Madabushi, A., Shi, G., Wilson, G. M., & Lu, A-L. Association of the Rad9-Rad1-Hus1 checkpoint clamp with MYH DNA glycosylase and DNA. DNA Repair, 31; 80-90, 2015. [PMCID: PMC4458174] [PMID: 26021743]

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 SIRT6 histone deacetylase. Her group has proposed that 9-1-1 serves as a platform to regulate BER processes (Fig. 1). The proteins involved in DNA repair and DNA damage are “care keepers” 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). SIRT6 is an aging regulator. Moreover, thymine DNA glycosylase (TDG), AP endonuclease (APE1), and 9-1-1 are essential for embryonic development. Her laboratory has applied the inhibitors of the factors involved in DNA repair and DNA damage response for therapeutic treatments to breast cancer and melanoma. Her laboratory has published that combined treatments with SIRT1 inhibitors (SIRT1i) with temozolomide (TMZ) and 5-florouracil (5FU) show synergistic reduction of cell viability and colony formation of breast cancer cells. They also show that a specific SIRT1 and a BRAF inhibitor (BRAFi) can synergistically inhibit melanoma cell viability and the SIRT1 inhibitor can reduce the growth of melanoma tumor in mouse xenografts. Moreover, their recent novel findings show that a Chk1 inhibitor (CHK1i) can decrease cell growth and overcome the resistance to BRAFi of BRAFi-resistant melanoma cells.

Grants and Contracts

Ongoing Research Support

2014-MSCRFE-0656                                                                                      Lu-Chang (PI)                                                 07/01/2014–11/30/2016                                        

Maryland Stem Cell Research Fund                                                                                                                    *Currently No Cost Extension

The effects of histone deacetylation and DNA demethylation on somatic cell reprogramming

The goal of this project is to enhance the induction efficiency and quality of induced pluripotent stem cells (iPSCs) by altering epigenetic state of somatic cells through modulating the activities of several key epigenetic and DNA repair regulators including SIRT1 and TDG.

Role: PI

Completed Research Support in past 3 years

R01 CA078391-16                                                                                          Lu-Chang (PI)                                        09/01/2009-01/31/2015                      

Repair of Oxidatively Damaged Guanines

The major goal of this project is to study the interactions among DNA repair proteins, cell cycle checkpoint proteins, and histone deacetylases.

Role: PI

Pending Grant

R01 GM118837-01A1                                                                                    Lu-Chang (PI)                                        12/01/2016-11/30/2021

The role of the checkpoint clamp in DNA repair

The goal of this project is to define the biochemical and functional relationships between 9-1-1 and two enzymes (MYH and APE1) that mediate initial steps of BER.

Role: PI

(Received 9th percentile)

Professional Activity

Professional memberships

 

1985               American Society for Microbiology

1991                American Association for the Advancement of Science

1993                Society of Chinese Bioscientists in America

1998                Society of Genetics

2000                American Society for Biochemistry and Molecular Biology

 

Admission Service                                                                                                                            

Institutional Service

1995-1997       Member, Graduate Council

1995-1997       Member, LongRange Planning and New Programs Committee

1995-1997       Member, Grievance Committee

1988                Member, Faculty Search Committee, Dept. Biochemistry and Molecular Biology

1988-1991       Member, Study Panels of the Short Term Research Training Program (STRTP), School of Medicine, University of Maryland

1988-1991       Member, SRIS/GRA Review Panel, School of Medicine, University of Maryland

1990-1992       Member, Bressler/Pangborn Review Panel

1992                Member, Faculty Search Committee, Dept. Biochemistry and Molecular Biology

1996                Member, Intramural Grant Study Section

1996                Member, Departmental Review Committee

1997                Member, Faculty Search Committee, Dept. Biochemistry and Molecular Biology

2001                Member, Intramural Grant Study Section

2001-2003       Member, APT Committee, Dept. Biochemistry and Molecular Biology

1985-present   Member, Departmental Graduate Education Committee

1994-2007       Member, Governing Committee, Joint Program of Dept. Biochemistry and Molecular Biology of UMB and Dept. Chemistry, UMBC

2003-2007       Member, School of Medicine Council, University of MarylandSchool of Medicine

2005-2007       Member, APT Committee, University of MarylandSchool of Medicine

2006                Member, Search Committee for the chairperson of Dept. Microbiology and Immunology

2007                Member, Departmental Executive Committee

2007                Member, APT Appeals Committee, University of MarylandSchool of Medicine

2007-2012       Chair, Departmental APT Committee

2008-present   Member, Departmental Faulty Search Committee

2007-present Member, Biochemistry and Molecular Biology Instrumentation Core Oversight Committee

2012                Judge, 3rd Annual Cancer Biology Retreat

21013              Member, UMB Structural Biology Shared Service Committee

2015-present   Member, APT Committee, Dept. Biochemistry and Molecular Biology

 

 

National and International Service

1997-present   Editorial Board Member, Taiwania

2002-present   Editorial Board Member, Frontiers in Bioscience

2001-present   Editorial Board Member, Medical Science Monitor

2009-present   Editorial Board Member, Enzyme Research

1990                Member, Review Panel, NIH Minority Biomedical Research Support (MBRS) Program

1993                Grant Reviewer, NSF

1993                Member, Ad Hoc Study Section, NIH Microbial Physiology and Genetics,

1994                Site visit team member, National Cancer Institute

1994                President, Washington DC/Baltimore chapter of Society of Chinese Bioscientists in America (SCBA)

1994                Co-organizer, 1st Annual Joint Scientific symposium of NIH/FDA CAA and Washington DC chapter of SCBA, June 25,.

1996                Site visit team member, National Cancer Institute

1997                Tele-conference team member, National Cancer Institute

1995-1999       Member, Study Section, NIH Microbial Physiology and Genetics

2000                Site visit team member, National Cancer Institute, February

2003                Site visit team member, National Institute of Environmental Health Sciences

2004                Tele-conference team member, National Cancer Institute Special Emphasis Panel

2005                Grant Reviewer, National Institute of Environmental Health Sciences, Superfund basic research and training program

2007                Member, Advisory committee, International conference in cellular response to DNA damage. National Tsing-Hua University, Taiwan

2007                Section chair, International conference in cellular response to DNA damage. National Tsing-Hua University, Taiwan

2008                Grant Reviewer, National Research Agency, Physics and Chemistry for Life Sciences (France)

2008                Ad Hoc Member, NIH Molecular Genetics C Study Section

2013                Ad Hoc Member, Qatar National Research Fund, Qatar

2014                Co-organizer, 6th Baltimore Area Repair Symposium

2014                Ad Hoc Member, Qatar National Research Fund, Qatar

1985-present   Journal Referee:  Journal of Bacteriology, Biochemistry, Journal of Biological Chemistry, Biochemistry Journal, EMBO Journal, Genetics, Nucleic Acid Research, Medical Science Monitor, FEMS Microbiology Letters, Cancer letter, Oncogene, Journal of Biochemistry, Biochemical Journal, DNA repair, Carcinogenesis, Frontier in Bioscience, PosOne

Lab Techniques and Equipment

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.