Molecular Biosciences

Changshun Shao
Associate Research Professor

Rutgers University
Department of Genetics
Nelson Lab, Room B428
Piscataway, NJ 08854
(848) 445-5406
FAX - (732) 445-1147

Biological responses to DNA damage, mutagenesis and tumorigenesis

Mutations contribute to genetic diversity and evolution. Mutations in somatic cells, especially those in stem cells, may lead to abnormalities in proliferation, differentiation, homeostasis and tissue function. Some mutations, when occurring in the right combination and in the right temporal order, will lead to the formation of cancer. We are characterizing the mechanisms by which somatic mutations are generated and accumulated in vivo, using mice as a model organism. We are also examining the biological mechanisms that underlie the development and progression of tumors, especially lymphomas and intestinal adenomas, in cancer-prone mouse models.

DNA repair and somatic mutation

Cells will frequently encounter numerous types of DNA lesions, such as base damage, mismatches, single-strand breaks and double-strand breaks. Various sophisticated DNA repair pathways have been evolved to deal with those DNA lesions. What would happen if a DNA repair pathway is defective or absent? We are determining the genetic consequences, in terms of somatic mutation and tumorigenesis, caused by defective DNA repair pathways in vivo. Our studies showed that somatic mutations are accumulated differentially in different cell types in vivo. We are determining whether the pathways and the activities of DNA repair are varied with developmental stages and cell types, and thus contribute to the differential accumulation.

Cell death as a safeguard of genome stability

DNA damage, shortened telomeres or inappropriate activation of oncogenes can all induce cell death, by the means of apoptosis or senescence. Cells harboring such misshapenness, if not eliminated, are at a great risk of accumulating new mutations and turning into preneoplastic cells. Therefore, although cell death may cause tissue injury or aging, it serves as a safeguard against mutagenesis and tumorigenesis. The somatic mutations that arise in experimental conditions of reduced or enhanced cell death are being characterized. Findings from such studies will provide important insights into the mechanisms underlying tumor initiation.

Genetic factors in the modulation of tumorigenesis in ApcMin mice

Patients of familial adenomatous polyposis (FAP) and ApcMin/+ mice, a model for FAP, develop adenomas at a high frequency in their intestines due to functional loss of APC, which negatively regulates Wnt signaling pathway. DNA hypomethylation, rendered by Dnmt1 mutation or by treatment with DNA demethylating agents, can suppress intestinal tumorigenesis in Apcmin/+ mice and in other cancer models. We are exploring the candidate factors that are responsible for the down regulation of Wnt/beta-catenin signaling pathway. Findings obtained from this model system may provide valuable clues to cancer prevention and cancer treatment.

Selected Publications

Rani V, Neumann CA, Shao C, Tischfield JA. (2012) Prdx1 deficiency in mice promotes tissue specific loss of heterozygosity mediated by deficiency in DNA repair and increased oxidative stress. Mutat Res. May 11. [Epub ahead of print]

Liu Y, Deng L, Nguyen SC, Au CL, Shao C, Tischfield JA, Liang L. (2012) A human cell-based reporter detects microhomology-mediated end joining. Mutat Res. Mar 1;731(1-2):140-4.

Wang X, Chen T, Leng L, Fan J, Cao K, Duan Z, Zhang X, Shao C, Wu M, Tadmori I, Li T, Liang L, Sun D, Zheng S, Meinhardt A, Young W, Bucala R, Ren Y. (2012) MIF produced by bone marrow-derived macrophages contributes to teratoma progression after embryonic stem cell transplantation. Cancer Res. Jun 1;72(11):2867-2878.

Xu B, Sun Z, Liu Z, Guo H, Liu Q, Jiang H, Zou Y, Gong Y, Tischfield JA, Shao C. (2011) Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. PLoS One. Apr 15;6(4):e18618.

Denissova NG, Tereshchenko IV, Cui E, Stambrook PJ, Shao C, Tischfield JA. (2011) Ionizing radiation is a potent inducer of mitotic recombination in mouse embryonic stem cells. Mutat Res. Oct 1;715(1-2):1-6.

Sun Z, Han Q, Zhu Y, Li Z, Chen B, Liao L, Bian C, Li J, Shao C, Zhao RC. (2011) NANOG Has a Role in Mesenchymal Stem Cells' Immunomodulatory Effect. Stem Cells Dev. 20(9):1521-8.

Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J, Wei JJ. (2011) HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res. Jan 15;71(2):349-59.

Lin P, Mao F, Liu Q, Shao C, Yan C, Gong Y. (2010) Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG42) caused by SLC33A1 mutation in a Chinese kindred.
Prenat Diagn. May;30(5):485-6.

Tereshchenko IV, Chen Y, McDaniel LD, Schultz RA, Tischfield JA, Shao C. (2010)Small scale genetic alterations contribute to increased mutability at the X-linked Hprt locus in vivo in Blm hypomorphic mice. DNA Repair (Amst). May 4;9(5):551-7.

Ren G, Zhao X, Zhang L, Zhang J, L'Huillier A, Ling W, Roberts AI, Le AD, Shi S, Shao C, Shi Y. (2010) Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol. 184(5):2321-8.

Zhao X, Ren G, Liang L, Ai PZ, Zheng B, Tischfield JA, Shi Y, Shao C. (2009) Brief Report-IFNgamma induces expansion of Lin-Sca-1+C-Kit+ cells. Stem Cells. 28(1):122-6.

Zou Y, Mi J, Cui J, Lu D, Zhang X, Guo C, Gao G, Liu Q, Chen B, Shao C, Gong Y. (2009) Characterization of nuclear localization signal in the N terminus of CUL4B and its essential role in cyclin E degradation and cell cycle progression. J Biol Chem. 284(48):33320-32.

Shao C, Liang L, Zhao X, Chen Y, Zheng B, Chen J, Luo M, Tischfield JA. (2009) Mutagenesis in vivo in T cells of p21-deficient mice. Mutat Res. 670(1-2):103-6.

Zhou H, Shang L, Li X, Zhang X, Gao G, Guo C, Chen B, Liu Q, Gong Y, Shao C. 2009) Resveratrol augments the canonical Wnt signaling pathway in promoting osteoblastic differentiation of multipotent mesenchymal cells. Exp Cell Res. 315(17):2953-62.

Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, Li J, Yan X, Liu Y, Shao C, Zhao RC. (2009) Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia. 23(5):925-33.

Shang L, Zhou H, Xia Y, Wang H, Gao G, Chen B, Liu Q, Shao C, Gong Y. (2008) Serum withdrawal up-regulates human SIRT1 gene expression in a p53-dependent manner. J Cell Mol Med. Aug 9. [Epub ahead of print]

Liu Z, Liu Q, Xu B, Wu J, Guo C, Zhu F, Yang Q, Gao G, Gong Y, Shao C. (2009) Berberine induces p53-dependent cell cycle arrest and apoptosis of human osteosarcoma cells by inflicting DNA damage. Mutat Res. 662(1-2):75-83.

Lin P, Li J, Liu Q, Mao F, Li J, Qiu R, Hu H, Song Y, Yang Y, Gao G, Yan C, Yang W, Shao C, Gong Y. (2008) A missense mutation in SLC33A1, which encodes the acetyl-CoA transporter, causes autosomal-dominant spastic paraplegia (SPG42). Am J Hum Genet. 83(6):752-9.

Barrera-Oro J, Liu TY, Gorden E, Kucherlapati R, Shao C, Tischfield JA. (2008) Role of the mismatch repair gene, Msh6, in suppressing genome instability and radiation-induced mutations. Mutat Res. 642(1-2):74-9.

Liang L, Deng L, Nguyen SC, Zhao X, Maulion CD, Shao C, Tischfield JA. (2008) Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Res. 36(10):3297-310.

Liang L, Deng L, Mendonca MS, Chen Y, Zheng B, Stambrook PJ, Shao C, Tischfield JA. (2007) X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells. DNA Repair (Amst). 6(9):1380-5.

Zhu G, Ke X, Liu Q, Li J, Chen B, Shao C, Gong Y. (2007) Recurrence of the D100N mutation in a Chinese family with brachydactyly type A1: Evidence for a mutational hot spot in the Indian hedgehog gene. Am J Med Genet A. 143A(11):1246-8.

Liang L, Mendonca MS, Deng L, Nguyen SC, Shao C, Tischfield JA. (2007) Reduced apoptosis and increased deletion mutations at Aprt locus in vivo in mice exposed to repeated ionizing radiation. Cancer Res. 67(5):1910-7.

Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y. (2007) Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am J Hum Genet. 80(3):561-6.

Liang L. Deng L. Chen Y. Li GC. Shao C. Tischfield JA. (2005) Modulation of DNA end joining by nuclear proteins. J Biol Chem. 280(36):31442-9.

Shao C. Deng L. Chen Y. Kucherlapati R. Stambrook PJ. Tischfield JA. (2004). Mlh1 mediates tissue-specific regulation of mitotic recombination. Oncogene (in press).