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Laboratory of Binghui Shen, Ph.D.

The Shen laboratory has carried out various major National Institutes of Health-funded projects. In addition, we collaborate with Dr. Yuejin Hua of Zhejiang University, China, in the study of radiation-induced DNA damage responses in Deinococcus radiodurans.
 
Research Environment
The laboratory is located in the Beckman Research Institute at City of Hope in Duarte, California. Duarte is in the northeast suburbs of Los Angeles, just outside Pasadena, nestled in the foothills of the San Gabriel mountains. We're close to all of the entertainment and scenic attractions Southern California has to offer, yet far enough removed from the big city buzz. Take a half hour drive to the beach, or an hour and a half to local skiing. The medical center and Beckman Research Institute are situated on a beautiful, 112-acre campus, and our lab is housed in the Kaplan-Black Research Building.
 
Approximately 25 NCI-supported core facilities are available for biomedical research in City of Hope as a Comprehensive Cancer Center research facility. These include: microarray, mass-spectroscopy/protein sequencing, DNA sequencing, oligonucleotide & peptide synthesis, phosphor- and fluoro-imaging, histology/histochemistry, frozen tumor bank, time-lapse videography, confocal and electron microscopies, cytogenetics, NMR, flow-cytometry, molecular modeling, transgenic mice, and animal care.
 
An active Postdoctoral Association (PDA) promotes interaction between the Institute and postdoctoral fellows and graduate students, to help to ensure that their transition is smooth and their time here is as fulfilling as possible
 

Binghui Shen, Ph.D. Research

DNA Replication, Repair, and Apoptosis Nucleases in Genome Stability and Cancer
DNA replication and repair are critical for maintaining genome stability. These processes are in part dependent on the activities of an emerging family of structure-specific nucleases. Flap EndoNuclease 1 (FEN1) is a metallo- and substrate structure specific- nuclease. It possesses three distinct biochemical activities, functioning as a flap endonuclease (FEN), a nick-specific exonuclease (EXO), and a gapdependent endonuclease (GEN). FEN1 plays a critical role in maintaining human genome stability via six different pathways. It serves as a major nuclease for RNA primer removal during Okazaki fragment maturation and for long patch base excision repair using its FEN activity. Its concerted action of EXO and GEN activities is critical in resolution of di- and tri- nucleotide repeat secondary structures and stalled DNA replication forks, as well as in apoptotic cell DNA fragmentation. It also plays a major role in maintenance of telomere stability.
 
The multiple functions of FEN1 are regulated via three major mechanisms: formation of complexes with different protein partners, cellular compartmentation, and post-translational modifications. More than 30 proteins have been identified to interact with FEN1, forming specific complexes in different pathways. Upon acetylation, FEN1 translocates into the nucleus in response to DNA damage and cell cycle phase changes. It is very much enhanced in the nucleolus for maintenance of stability of tandem repeats of ribosomal DNA. FEN1 is also in mitochondrion, playing an important role in mitochondrial DNA replication and repair. The nuclease is acetylated, phosphorylated or methylated in different molecular events and the interaction between methylation and phosphorylation determines its recruitment onto DNA replication forks via proliferating cell nuclear antigen. The first group of FEN1 somatic mutations has been identified in human cancer cells, which has clear segregation of biochemical activities. The future emphasis will be placed on the mutations and prevalent polymorphisms that may impair one of the three major regulatory mechanisms. See Project 1  - Functional Analysis of FEN-1 Nuclease in Genome Stability.
 
Recently, we found that another major nuclease, DNA2, is dominantly localized into mitochondria and cooperatively processes replication and repair DNA intermediates for ligation and completion of circular mtDNA replication and repair. These novel and exciting observations prompted us to: i) knock out the DNA2 gene in mice to determine if defective DNA2-mediated RNA primer removal causes mitochondrial genomic instabilities, consequently promoting cancers and other genetic diseases, and ii) link functional defects of the DNA2 mutations identified in human mitochondrion-based diseases to pathologic mechanisms. Information made available from these studies should establish a relationship among the functions of these novel mitochondrial genes, unique mitochondrial mutagenic phenotype(s), and pathological mechanisms. The proposed study may also establish a foundation for the development of new treatment regimens for patients with mitochondrion-based cancers and other disorders. See Project 2 - Role of Nucleases in RNA Primer Removal and Mutagenesis.
 
The other novel nuclease that we are interested in is called TatD, which possesses a nick and 3’ exonuclease activity and is involved in apoptosis DNA fragmentation. In collaboration with Dr. John Williams in the Department of Molecular Medicine, we are currently undertaking a detailed 3-D structural and functional analysis of TatD to determine its role in apoptosis and the biological consequences, in human cells, of defects in this nuclease.
 

Binghui Shen, Ph.D. Project 1

Functional analysis of FEN1 nuclease in genome stability
The project was funded by NCI to test a hypothesis that subtle deficiency or defects in the individual biochemical activities of FEN1 may lead to different phenotypes in yeast and different susceptibilities in the human population to environmental stresses and individual differences in the onset of genetic diseases.
 
Figure to the right: E160D FEN1 mice are highly susceptible to cancers as a result of their mutator phenotype and chronic inflammation. The panel shows the chronic inflammation and Tumorigenesis in the lung. Top, disease incidence at specific life stages (timeline in months) of wild-type (WT), Fen1ED/+ (ED/+) and Fen1ED/ED (ED/ED) mice. Below, histology (H&E) of normal lung, lung with chronic inflammation, adenoma and adenocarcinoma in ED/ED mice. From: Zheng et al., 2008 Nature Medicine.
 

Binghui Shen, Ph.D. Project 2

Role of nuclease in RNA primer removal and mutagenesis
The major goals of this project are to carry out experiments to test roles of several eukaryotic nuclease complexes in RNA primer removal during lagging strand DNA synthesis in nuclei and mitochondria, and to examine the mutagenic consequences of defects of the individual nuclease complexes.
 
Localization of hDNA2 and mitochondria-lspecific heat-shock protein 70 (mtHSP70) in HeLa cells. hDNA2 (red) and mtHSP70 (green) were stained with antibodies to hDNA2 and mtHSP70. The nucleus (blue) was stained with DAPI. Yellow spots (arrows) indicate co-localization of hDNA2 and mtHSP70 (merged views). The square box in the upper right panel is a magnification of the area framed in white.
 

Binghui Shen, Ph.D. Laboratory Members

Huifang Dai, B.S.
Sr. Research Associate
Ph 626-256-HOPE (4673), ext. 63818
Fax 626-301-8892
hdai@coh.org
 
Joonas Jamsen, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext. (W/A)
Fax 626-301-8892
jjamsen@coh.org
 
Weiqiang Lin, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext.64146
Fax 626-301-8892
wlin@coh.org
 
Guojun Lin, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext. 63818
Fax 626-301-8892
glu@coh.org
 
David Onyango, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext. 65284
Fax 626-301-8892
donyango@coh.org
 
Julie Kanjanapangka
Graduate Student
Ph 626-256-HOPE (4673), ext. 62935
Fax 626-301-8892
jkanjanapangka@coh.org
 
Zhenxing Wu, M.S.
Predoctoral Fellow
Ph. 626-256-HOPE (4673), ext. 63518
Fax 626-301-8892
zhwu@coh.org
 
Li Zheng, Ph.D.
Assistant Research Professor
Ph 626-256-HOPE (4673), ext. 64147
Fax 626-301-8892
lzheng@coh.org
 
Mian Zhou, Ph.D.
Staff Scientist
Ph 626-256-HOPE (4673), ext. 64147
Fax 626-301-8892
mzhou@coh.org
 

Shen, Binghui, Ph.D.

Laboratory of Binghui Shen, Ph.D.

The Shen laboratory has carried out various major National Institutes of Health-funded projects. In addition, we collaborate with Dr. Yuejin Hua of Zhejiang University, China, in the study of radiation-induced DNA damage responses in Deinococcus radiodurans.
 
Research Environment
The laboratory is located in the Beckman Research Institute at City of Hope in Duarte, California. Duarte is in the northeast suburbs of Los Angeles, just outside Pasadena, nestled in the foothills of the San Gabriel mountains. We're close to all of the entertainment and scenic attractions Southern California has to offer, yet far enough removed from the big city buzz. Take a half hour drive to the beach, or an hour and a half to local skiing. The medical center and Beckman Research Institute are situated on a beautiful, 112-acre campus, and our lab is housed in the Kaplan-Black Research Building.
 
Approximately 25 NCI-supported core facilities are available for biomedical research in City of Hope as a Comprehensive Cancer Center research facility. These include: microarray, mass-spectroscopy/protein sequencing, DNA sequencing, oligonucleotide & peptide synthesis, phosphor- and fluoro-imaging, histology/histochemistry, frozen tumor bank, time-lapse videography, confocal and electron microscopies, cytogenetics, NMR, flow-cytometry, molecular modeling, transgenic mice, and animal care.
 
An active Postdoctoral Association (PDA) promotes interaction between the Institute and postdoctoral fellows and graduate students, to help to ensure that their transition is smooth and their time here is as fulfilling as possible
 

Research

Binghui Shen, Ph.D. Research

DNA Replication, Repair, and Apoptosis Nucleases in Genome Stability and Cancer
DNA replication and repair are critical for maintaining genome stability. These processes are in part dependent on the activities of an emerging family of structure-specific nucleases. Flap EndoNuclease 1 (FEN1) is a metallo- and substrate structure specific- nuclease. It possesses three distinct biochemical activities, functioning as a flap endonuclease (FEN), a nick-specific exonuclease (EXO), and a gapdependent endonuclease (GEN). FEN1 plays a critical role in maintaining human genome stability via six different pathways. It serves as a major nuclease for RNA primer removal during Okazaki fragment maturation and for long patch base excision repair using its FEN activity. Its concerted action of EXO and GEN activities is critical in resolution of di- and tri- nucleotide repeat secondary structures and stalled DNA replication forks, as well as in apoptotic cell DNA fragmentation. It also plays a major role in maintenance of telomere stability.
 
The multiple functions of FEN1 are regulated via three major mechanisms: formation of complexes with different protein partners, cellular compartmentation, and post-translational modifications. More than 30 proteins have been identified to interact with FEN1, forming specific complexes in different pathways. Upon acetylation, FEN1 translocates into the nucleus in response to DNA damage and cell cycle phase changes. It is very much enhanced in the nucleolus for maintenance of stability of tandem repeats of ribosomal DNA. FEN1 is also in mitochondrion, playing an important role in mitochondrial DNA replication and repair. The nuclease is acetylated, phosphorylated or methylated in different molecular events and the interaction between methylation and phosphorylation determines its recruitment onto DNA replication forks via proliferating cell nuclear antigen. The first group of FEN1 somatic mutations has been identified in human cancer cells, which has clear segregation of biochemical activities. The future emphasis will be placed on the mutations and prevalent polymorphisms that may impair one of the three major regulatory mechanisms. See Project 1  - Functional Analysis of FEN-1 Nuclease in Genome Stability.
 
Recently, we found that another major nuclease, DNA2, is dominantly localized into mitochondria and cooperatively processes replication and repair DNA intermediates for ligation and completion of circular mtDNA replication and repair. These novel and exciting observations prompted us to: i) knock out the DNA2 gene in mice to determine if defective DNA2-mediated RNA primer removal causes mitochondrial genomic instabilities, consequently promoting cancers and other genetic diseases, and ii) link functional defects of the DNA2 mutations identified in human mitochondrion-based diseases to pathologic mechanisms. Information made available from these studies should establish a relationship among the functions of these novel mitochondrial genes, unique mitochondrial mutagenic phenotype(s), and pathological mechanisms. The proposed study may also establish a foundation for the development of new treatment regimens for patients with mitochondrion-based cancers and other disorders. See Project 2 - Role of Nucleases in RNA Primer Removal and Mutagenesis.
 
The other novel nuclease that we are interested in is called TatD, which possesses a nick and 3’ exonuclease activity and is involved in apoptosis DNA fragmentation. In collaboration with Dr. John Williams in the Department of Molecular Medicine, we are currently undertaking a detailed 3-D structural and functional analysis of TatD to determine its role in apoptosis and the biological consequences, in human cells, of defects in this nuclease.
 

Project 1

Binghui Shen, Ph.D. Project 1

Functional analysis of FEN1 nuclease in genome stability
The project was funded by NCI to test a hypothesis that subtle deficiency or defects in the individual biochemical activities of FEN1 may lead to different phenotypes in yeast and different susceptibilities in the human population to environmental stresses and individual differences in the onset of genetic diseases.
 
Figure to the right: E160D FEN1 mice are highly susceptible to cancers as a result of their mutator phenotype and chronic inflammation. The panel shows the chronic inflammation and Tumorigenesis in the lung. Top, disease incidence at specific life stages (timeline in months) of wild-type (WT), Fen1ED/+ (ED/+) and Fen1ED/ED (ED/ED) mice. Below, histology (H&E) of normal lung, lung with chronic inflammation, adenoma and adenocarcinoma in ED/ED mice. From: Zheng et al., 2008 Nature Medicine.
 

Project 2

Binghui Shen, Ph.D. Project 2

Role of nuclease in RNA primer removal and mutagenesis
The major goals of this project are to carry out experiments to test roles of several eukaryotic nuclease complexes in RNA primer removal during lagging strand DNA synthesis in nuclei and mitochondria, and to examine the mutagenic consequences of defects of the individual nuclease complexes.
 
Localization of hDNA2 and mitochondria-lspecific heat-shock protein 70 (mtHSP70) in HeLa cells. hDNA2 (red) and mtHSP70 (green) were stained with antibodies to hDNA2 and mtHSP70. The nucleus (blue) was stained with DAPI. Yellow spots (arrows) indicate co-localization of hDNA2 and mtHSP70 (merged views). The square box in the upper right panel is a magnification of the area framed in white.
 

Lab Members

Binghui Shen, Ph.D. Laboratory Members

Huifang Dai, B.S.
Sr. Research Associate
Ph 626-256-HOPE (4673), ext. 63818
Fax 626-301-8892
hdai@coh.org
 
Joonas Jamsen, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext. (W/A)
Fax 626-301-8892
jjamsen@coh.org
 
Weiqiang Lin, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext.64146
Fax 626-301-8892
wlin@coh.org
 
Guojun Lin, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext. 63818
Fax 626-301-8892
glu@coh.org
 
David Onyango, Ph.D.
Postdoctoral Fellow
Ph. 626-256-HOPE (4673), ext. 65284
Fax 626-301-8892
donyango@coh.org
 
Julie Kanjanapangka
Graduate Student
Ph 626-256-HOPE (4673), ext. 62935
Fax 626-301-8892
jkanjanapangka@coh.org
 
Zhenxing Wu, M.S.
Predoctoral Fellow
Ph. 626-256-HOPE (4673), ext. 63518
Fax 626-301-8892
zhwu@coh.org
 
Li Zheng, Ph.D.
Assistant Research Professor
Ph 626-256-HOPE (4673), ext. 64147
Fax 626-301-8892
lzheng@coh.org
 
Mian Zhou, Ph.D.
Staff Scientist
Ph 626-256-HOPE (4673), ext. 64147
Fax 626-301-8892
mzhou@coh.org
 
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Our research laboratories are led by the best and brightest minds in scientific research.
 

Beckman Research Institute of City of Hope is internationally  recognized for its innovative biomedical research.
City of Hope is one of only 41 Comprehensive Cancer Centers in the country, the highest designation awarded by the National Cancer Institute to institutions that lead the way in cancer research, treatment, prevention and professional education.
Learn more about City of Hope's institutional distinctions, breakthrough innovations and collaborations.
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