DNA double stranded breaks (DSBs) are critical lesions that can cause significant alterations 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.