Division Head: Molecular Biology
Research Interests: Mechanisms of mammalian DNA double-strand break repair
Our objective is to gain an understanding of the molecular and biochemical mechanisms of mammalian DNA double-strand break (DSB) repair. The importance of DNA DSB repair is underscored by the existence of human cancer predisposition diseases, such as Nijmegen chromosome breakage syndrome, ataxia telangiectasia and Fanconi's anemia, which are caused by defects in DNA repair. The high cancer rate associated with these and other human diseases suggests that generalized DNA repair is also critical for many other important biological processes including immune system development, as well as chromosome integrity and stability. In particular, we have shown that DNA DSB repair is also required for telomere maintenance and have demonstrated that defects in DNA DSB repair genes lead to telomere dysfunction and genomic instability. Our basic experimental model system uses recombinant adeno-associated virus- and Cas/CRISPR-mediated gene targeting techniques in human cell lines in culture. In summary, the identification and characterization of the genes and protein factors involved in DSB repair will provide insight into the general mechanisms of DNA recombination and DNA repair and could have therapeutic significance for many types of immune disorders and cancers as well as improving gene therapy methodologies.
Hendrickson, E. A., and Baird, D. Alternative end-joining, clonal evolution and the escape from a telomere-driven crisis. (2015) Mol. Cell. Oncol., in press.
Thangavel, S., Berti, M., Levikova, M., Moore, H., Gomathinayagam, S., Vujanovic, M., Pinto, C., Lee, E. H., Hendrickson, E. A., Cejka, P., Stewart, S., Lopes, M. and Vindigni, A. DNA2 and WRN coordinate replication restart by processing reversed replication forks. (2015) J. Cell Biol., in press.
Ghezraoui, H., Piganeau, M., Renouf, B., Renaud, J.-B., Sallmyr, A., Ruis, B., Oh, S., Tomkinson, A., Hendrickson, E. A., Giovannangeli, C., Jasin, M. and Brunet, E. Chromosomal translocations in human cells occur by canonical nonhomologous end-joining. (2014) Mol. Cell, in press.
Jones, R. E., Oh, S., Grimstead, J., Zimbric, J., Roger, L., Hepple, N., Ashelford, K. E., Liddiard, K., Hendrickson, E. A. and Baird, D. M. Escape from telomere-driven crisis is DNA ligase III dependent. (2014) Cell Reports, in press.
Oh, S., Harvey, A., Zimbric, J., Wang, Y., Nguyen, T., Jackson, P. J. and Hendrickson, E. A. DNA ligase III and DNA ligase IV carry out genetically distinct forms of end joining in human somatic cell. (2014) DNA Repair, in press.
Waters, C. A., Strande, N. T., Pryor, J. M., Storm, C., Burkhalter, M., Oh, S., Mieczkowski, P., Hendrickson, E. A. and Ramsden, D. A. Ligation step fidelity determines how cellular nonhomologous end joining resolves mispaired and damaged ends. (2014) Nature Comm., 5, 4286.
Yeo, J. E., Lee, E. H., Baer, R., Hendrickson, E. A. and Sobeck, A. CtIP mediates replication fork recovery in a FANCD2-regulated manner. (2014) Human Mol. Genet., 23, 3695-3705.
Karanja, K. K., Lee, E. H., Hendrickson, E. A. and Campbell, J. Depletion of DNA2 helicase/nuclease suppresses the ICL and formaldehyde sensitivity of FANCD2-deficient cells. (2014) Cell Cycle, 13, 1540-1550.
Kan, Y., Ruis, B., Lin, S. and Hendrickson, E. A. The mechanism of gene targeting in human somatic cells. (2014) PLoS Genet., 10, e1004251.
Fattah, F., Kweon, J., Wang, Y., Lee, E. H., Lichter, N., Weisensel, N. and Hendrickson, E. A. A role for XLF in DNA repair and recombination in human somatic cells. (2014) DNA Repair, 15, 39-53.
Smith, S., Fox, J., Mejia, M., Ruangpradt, W., Saberi, A., Kim, S., Choi, Y., Oh, S., Wang, Y., Choi, K., Li, L., Hendrickson, E. A., Takeda, S., Muller, M. and Myung, K. Histone deacetylase inhibitors synergize with defects in DNA repair to kill cancer cells. (2014) PLoS ONE, 9, e87203.
Oh, S., Wang, Y., Zimbric, J. and Hendrickson, E. A. Human LIGIV is synthetically lethal with the loss of RAD54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction. (2013) Nucl. Acids Res., 41, 1734-1749.
Schumacher, A. J., Mohni, K. N., Kan, Y., Hendrickson, E. A., Stark, J. M., and Weller, S. K. The HSV-1 exonuclease, UL12, stimulates recombination by a single strand annealing mechanism. (2012) PLoS Path., 8, e1002862.
Strande, N., Roberts, S. A., Oh, S., Hendrickson, E. A. and Ramsden, D. A. Specificity of Ku’s dRP/AP lyase promotes nonhomologous end joining (NHEJ) fidelity at damaged ends. (2012) J. Biol. Chem., 287, 13686-13693.
Fattah, F., Lee, E. H., Weisensel, N., Wang, Y., Lichter, N., and Hendrickson, E. A. Ku regulates the non-homologous end joining pathway choice of double-strand breaks in human somatic cells. (2010) PLoS Genetics, 6, e1000855. PMID 20195511.
Wang, Y., Ghosh, G., and Hendrickson, E. A. Ku86 represses lethal telomere deletion events in human somatic cells. (2009) Proc. Natl. Acad. Sci., USA, 106, 1243-12435. PMID 19581589.
Ruis, B., Fattah, K. R., and Hendrickson, E. A. DNA-PKcs regulates proliferation, telomere length and genomic stability in human somatic cells. (2008) Mol. Cell. Biol., 28, 6182-6195.
Fattah, F., Lichter, N., Fattah, K. R., Oh, S., and Hendrickson, E. A. Ku70, an essential gene, modulates the frequency of rAAV-mediated gene targeting in human somatic cells. (2008) Proc. Natl. Acad. Sci., USA, 105, 8703-8708.
Hendrickson, E. A. Gene targeting in human somatic cells. (2008) In: Sourcebook of Models for Biomedical Research. M. Conn, Ed., Humana Press, Totowa, NJ, pp. 509-525 (REVIEW).
Hendrickson, E. A., Huffman, J. and Tainer, J. A. Structural aspects of Ku and the DNA dependent protein kinase complex. (2006) In: DNA Damage Recognition. W. Seide, Y. W. Kow and P. W. Doetsch, Eds., Taylor & Francis Group, Inc., Boca Raton, FL, pp. 629-684 (REVIEW).