DNA damage response pathway, Mitochondrial homeostasis, Tumor suppressor gene
Chen lab is interested in understanding the critical role of tumor suppressor genes in the genesis and progression of cancer. Currently, we are putting most of their efforts into elucidating the intracellular signaling pathways involved in the DNA damage response. We are focusing on molecules serving as transducers and effectors, including BRCA1 and BRCA2, members of the BRCT motif-containing family proteins such as NBS1, 53BP1 and NFBD1, and on the DNA repair machinery. Understanding these signal pathways is vital for solving the puzzle of how cells maintain their genome stability and how specific problems with DNA repair predispose to different cell type-specific cancers.
Wang DD, Guo XE, Modrek AS, Chen CF, Chen P-L, Lee WH. Helicase SUV3, Polynucleotide Phosphorylase, and Mitochondrial Polyadenylation Polymerase Form a Transient Complex to Modulate Mitochondrial mRNA Polyadenylated Tail Lengths in Response to Energetic Changes J Biol Chem. 289: 16727–16735. (2014)
Chen Y*, Chen CF, Polci R, Wei R, Riley DJ, Chen P-L. Increased Nek1 expression in renal cell carcinoma cells is associated with decreased sensitivity to DNA-damaging treatment. Oncotarget. 5:4283-4294. (2014)
Bothmer A, Rommel PC, Gazumyan A, Polato F, Reczek CR, Muellenbeck MF, Schaetzlein S, Edelmann W, Chen P-L, Brosh RM Jr, Casellas R, Ludwig T, Baer R, Nussenzweig A, Nussenzweig MC, Robbiani DF. Mechanism of DNA resection during intrachromosomal recombination and immunoglobulin class switching. J Exp Med. 210:115-23. doi: 10.1084/jem.20121975. Epub 2012 Dec 17. (2013)
Zhu J, Zhou L, Wu G, Konig H, Lin X, Li G, Qiu XL, Chen CF, Hu CM, Goldblatt E, Bhatia R, Chamberlin AR, Chen P-L, Lee WH*. A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia. EMBO Mol Med. 5(3):353-65. doi: 10.1002/emmm.201201760. Epub 2013 Jan 22. PMID: 23341130 (2013)
Chen PL, Chen CF, Chen Y, Guo XE, Huang CK, Shew JY, Reddick RL, Wallace DC, Lee WH. Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan. Oncogene. 2013 Feb 28;32(9):1193-201. doi: 10.1038/onc.2012.120. Epub 2012 May 7. PMID: 22562243
Wei PC, Hsieh YH, Su MI, Jiang X, Hsu PH, Lo WT, Weng JY, Jeng YM, Wang JM, Chen P-L, Chang YC, Lee KF, Tsai MD, Shew JY, Lee WH. Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease. Mol Cell. 2012 Dec 14;48(5):747-59. doi: 10.1016/j.molcel.2012.10.007. Epub 2012 Nov 1.PMID: 23123197.
Guo XE, Chen CF, Wang DD, Modrek AS, Phan VH, Lee WH, Chen P-L. Uncoupling the roles of the SUV3 helicase in maintenance of mitochondrial genome stability and RNA degradation. J Biol Chem. 2011 Sep 12.
Chen Y, Chen CF, Riley DJ, Chen P-L. Nek1 kinase functions in DNA damage response and checkpoint control through a pathway independent of ATM and ATR. Cell Cycle. 10:655-663. (2011).
Chen Y, Chen CF, Chiang HC, Pena M, Polci R, Wei RL, Edwards RA, Hansel DE, Chen P-L, Riley DJ. Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability. Mol Cancer. 10:5. (2011)
Gu B and Chen P-L. Expression of PCNA-binding domain of CtIP, a motif required for CtIP localization at DNA replication foci, causes DNA damage and activation of DNA damage checkpoint. Cell Cycle. 8: 1409-1420. (2009)
Wang DD, Shu Z, Lieser SA, Chen P-L, and Lee WH. Human Mitochondrial SUV3 and Polynucleotide Phosphorylase Form a 330-kDa Heteropentamer to Cooperatively Degrade Double-stranded RNA with a 3'-to-5' Directionality. J Biol Chem 284:20812-21. (2009)
Qiu XL, Li G, Wu G, Zhu J, Zhou L, Chen P-L, Chamberlin AR and Lee WH. Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues.J Med Chem. 52:1757-1767. (2009)
Chen Y, Chen P-L, Chen CF, Jiang X, Riley DJ. Never-in-mitosis related kinase 1 functions in DNA damage response and checkpoint control. Cell Cycle. 7:3194-3201. (2008)
Fang L, Wang X, Yamoah K, Chen P-L, Pan ZQ, Huang L. Characterization of the human COP9 signalosome complex using affinity purification and mass spectrometry. J Proteome Res. 7:4914-2495. (2008)
Wu G, Qiu XL, Zhou L, Zhu J, Chamberlin R, Lau J, Chen PL and Lee WH Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. Cancer Res. 68:8393-8399. (2008)
Wu G and Chen P-L. Structural requirements of chromokinesin Kif4A for its proper mitotic. Biochem Biophys Res Commun, 372:454-458. (2008)
Wu G, Khidr L, Zhou L, Kim W, Lee YM, Krasieva T and Chen P-L. A novel role of the chromokinesin Kif4A in DNA damage response. Cell Cycle, 7:2013-2020. (2008)
Tawara H, Fujiuchi N, Sironi J, Martin S, Aglipay J, Ouchi M, Taga M, Chen P-L, Ouchi T: Loss of p53-regulatory protein IFI16 induces NBS1 leading to activation of p53-mediated checkpoint by phosphorylation of p53 ser37. Front Biosci. 13:240-248. (2008)
Jeng YM, Cai-Ng S, Li A, Furuta S, Chew H, Chen P-L, Lee EY, Lee WH. Brca1 heterozygous mice have shortened life span and are prone to ovarian tumorigenesis with haploinsufficiency upon ionizing irradiation. Oncogene. 26:6160-6166. (2007)
Wang X, Chen CF, Baker PR, Chen P-L, Kaiser P, Huang L.: Mass spectrometric characterization of the affinity-purified human 26S proteasome complex. Biochemistry. 46:3553-3565. (2007)
Furuta S, Wang JM, Wei S, Jeng YM, Jiang X, Gu B, Chen P-L, Lee EY, Lee WH.: Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. Cancer Cell. 10:13-24. (2006)
Furuta S, Jiang X, Gu B, Cheng E, Chen P-L, Lee W-H.: Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. Proc Natl Acad Sci U S A. 102:9176-81. (2005)
Peng A and Chen P-L: NFBD1/Mdc1 mediates ATR-dependent DNA damage response. Cancer Res. 65:1158-1156 (2005).
Chen P-L, Liu F, Cai S, Lin X, Li A, Chen Y, Gu B, Lee EY, Lee W: Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol. 25:3535-3542 (2005).
Utomo A, Jiang X, Furuta S, Yun J, Levin DS, Wang YC, Desai KV, Green JE, Chen P-L, Lee WH.: Identification of a novel putative non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) essential for alleviating oxidative stress generated from polyunsaturated fatty acids in breast cancer cells. J Biol Chem. 279:43522-43529. (2004)
Shu Z, Vijayakumar S, Chen C-F, Chen P-L, and Lee W-H. Purified human SUV3p exhibits multiple-substrate unwinding activity upon conformational change. Biochemistry 43:4781-4790 (2004).
Polci R, Peng A, Chen P-L, Riley DJ, Chen Y: NIMA-related Protein Kinase 1 Is Involved Early in the Ionizing Radiation-Induced DNA Damage Response. Cancer Res. 64: 8800-8803 (2004).
Wu G-K, Jiang X-Z, Lee W-H, and Chen P-L: Assembly of functional ALT associated PML bodies requires NBS1. Cancer Res., 63: 2589-2595 (2003).
Peng A and Chen P-L: NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. J. Biol. Chem., 278: 8873-8876 (2003).