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DNA double stranded breaks (DSBs) are critical lesions that can causealterations in genetic information required for cell survival and proliferation. Aberrant DSB repair can impact on various pathologies, including acceleration of aging and the development of cancer.
The broad research focus of the Yan laboratory is to elucidate the fundamental mechanisms that maintain genomic stability in mammalian cells. Our lab uses a number of mouse strains that are prone to cancer because they are deficient or are engineered to conditionally inactivate or significantly impair genes that encode factors involved in DSB detection and repair. In particular, we are investigating the functions of the DSB repair pathway nonhomologous end joining (NHEJ), which repairs broken DNA ends irrespective of sequence homology. Our interests are to understand how defective NHEJ impacts on immunodeficiency and aging related pathologies, including immune system decline, stem cell dysfunction and cancer. We seek to clarify the genomic stability maintenance functions of NHEJ, by elucidating aberrant NHEJ outcomes. We seek to identify novel factors that promote aberrant end-joining and oncogenic translocations in the absence of NHEJ; also their impact on genomic alterations and mechanisms that lead to the malignant phenotype and relevance to human pathologies. In this context, we are developing novel cell based, molecular and biochemical experimental approaches to create a roadmap of genomic alterations that promote malignant transformation. We are also adapting these experimental approaches to investigate how accumulated decline in genome stability control impacts on cellular and organismal aging and age-related disease.
Yan C, Kaushal D, Murphy MM, Datta A, Lee CZ, Monroe B, Mostoslavsky G, Coakley K, Gao Y, Mills KD, Fazeli A, Tepsuporn S, Mulligan R, Fox E., Bronson R, De Gerolami U, Lee C, Alt FW (2006). XRCC4 suppresses medulloblastomas with recurrent translocations in p53 deficient mice. Proc. Natl. Acad. Sci. USA, 2006, 103 (19): 7378-7383.
Chaudhuri J, Basu U, Zarrin A, Yan C, Franco S, Perlot T, Vuong B, Wang J, Phan RT, Datta A, Manis J, and Alt FW. Evolution of the Immunoglobulin Heavy Chain Class Switch Recombination Mechanism. Advances in Immunology, 2007, 94:157-214.
Yan CT, Souza EK, Franco S, Hickernell T, Boboila C, Gumaste S, Geyer M, Manis JP, Rajewsky K and Alt, FW. IgH Class Switching and Chromosomal Translocations Employ a Robust Non-classical End-joining Pathway. Nature, 2007, 449 (7161):478-82.
Xie A., Hartlerode A, Stucki M, Odate S, Puget N, Naragju G, Yan C, Alt FW, Chen J, Jackson SP and Scully R. Multistep assembly of γ-H2AX chromatin domain reveals distinct functions of MDC1, 53BP1 and BRCA1 in recombination control. Molecular Cell, 2007, 28:1045-57.
Wang JH*,Alt FW, Datta A, Gostissa M, Murphy M, Coakley K, Goff P, Hickernell T Alimzhanov M, Casola S, Kutok J, Astor J, Bronson R, Manis JP, Rajewsky K, and Yan, CT*.Oncogenic transformation of editing and switching peripheral B cells in the absence of end-joining and p53. Journal Exp.Med, 2008, 205:3079-90. (*equal contribution).
Wang, JH*, Gostissa M*, Yan CT*, Goff P, Hickernell, T, Hansen E, Difilippantonio S, Wesemann, DR Zarrin AA, Rajewsky K, Nussenzweig A, and Alt, FW. Mechanisms promoting translocations in editing and switching peripheral B cells. (2009 Nature article, in press, *equal contribution).