DNA holds the information encoding molecules that confer cellular identity and direct cellular functions. This genetic material is constantly broken by exogenous and endogenous factors and must be repaired to preserve cellular identity and function. DNA double strand breaks (DSBs) are hazardous cellular lesions. Unfortunately, they also are very common. DSBs arise in every S phase through DNA replication errors and can be induced in any cell cycle phase by exogenous factors such as ionizing radiation or endogenous factors such as endonucleases or reactive oxygen species. When DSBs are mis-repaired, the resultant genomic instability can lead to cellular death or drive malignant transformation. Despite their danger, DSBs are a necessary part of biology. For example, the induction and repair of DSBs within antigen receptor loci during V(D)J recombination and immunoglobulin class switch recombination (CSR) is essential for development and function of an immune system capable of adapting and responding to a wide variety of pathogens. Cells have evolved efficient, specialized, and redundant mechanisms to sense, respond to, and repair DSBs. This generally conserved DNA damage response (DDR) integrates cell cycle progression and cellular survival to facilitate repair, or trigger apoptosis or senescence if damage is too severe. The physiological importance of V(D)J recombination and CSR control mechanisms has been demonstrated by the fact that defects in each can lead to immunodeficiency, autoimmunity, and lymphoma; while the immunological relevance of DDR control mechanisms has been illustrated by observations that deficiency of these can lead to immunodeficiency and lymphomas with antigen receptor locus translocations.
One main research focus within the lab aims to elucidate molecular mechanisms through which the DDR maintains genomic stability and suppresses transformation in cells during V(D)J recombination, CSR, and DNA replication. Our long-term translational goal is to exploit the knowledge and animal models gained through these studies to design, develop, and test novel treatments for pediatric cancers that are more effective and less toxic than current clinical therapies. Another focus aims to elucidate the epigenetic mechanisms by which antigen receptor gene rearrangements are coordinated between homologous alleles and activated/silenced in a developmental stage-specific manner to maintain genomic stability and suppress cellular transformation during V(D)J recombination. A final focus within the lab aims to test our hypothesis that the molecular mechanisms that control antigen receptor gene rearrangements and the cellular DDR co-evolved in lymphocytes to ensure development of an effective adaptive immune system without conferring substantial predisposition to auto-immunity or cancer upon the host organism.