Changshun Shao
Assistant Research Professor

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

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).

Tischfield JA. Shao C. (2003). Somatic recombination redux. Nature Genetics 33: 5-6.

Cervantes RB. Stringer JR. Shao C. Tischfield JA. Stambrook PJ. (2002). Embryonic stem cells and somatic cells differ in mutation frequency and type. Proc. Natl. Acad. Sci. USA 99: 3586-3590.

Shao C. Yin M. Deng L. Stambrook PJ. Doetschman T. Tischfield JA. (2002). Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2-/- mice. Oncogene 21:2840-2845.

Shao C. Stambrook PJ. Tischfield JA. (2001). Mitotic recombination is suppressed by chromosomal divergence in hybrids of distantly related mouse strains. Nature Genetics 28:169-172.

Shao C. Deng L. Henegariu O. Liang L. Stambrook PJ. Tischfield JA. (2000). Chromosome instability contributes to loss of heterozygosity in mice lacking p53. Proc. Natl. Acad. Sci. USA 97:7405-7410.