Description of Research Expertise

Research Interests:

Elucidation of molecular mechanisms that: 1) mediate the cellular DNA damage response to maintain genomic stability and suppress malignant transformation, and 2) direct the assembly, modification, and silencing of lymphocyte antigen receptor genes to establish adaptive immunity without causing lymphoma or auto-immunity.


Key Words:

DNA repair, genomic instability, cancer, lymphocyte development, V(D)J recombination, class switch recombination, auto-immunity


Research Details:

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 reactive oxygen species. When un-repaired or mis-repaired, DSBs can result in genomic instability that can lead to cell death or drive malignant transformation. Despite their danger, DSBs are a necessary part of biology. In this context, the induction and repair of DSBs within antigen receptor loci during V(D)J recombination and 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 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. Another research focus within the lab aims to exploit the knowledge and animal models gained through these studies to design, develop, and test novel treatments for cancer that are more effective and less toxic than current clinical therapies. A third research 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. Another research 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 autoimmunity or cancer upon the host organism.


Current Lab Personnel:

Katherine Yang-Iott – CHOP Research Associate
Natalie Steinel – UPenn IGG Graduate Student
Amy DeMicco – UPenn CAMB Graduate Student
Julie Horowitz – UPenn IGG Graduate Student
Levi Rupp - UPenn CAMB Graduate Student
Lori Ehrlich – CHOP Hematology/Oncology Research Fellow


Former Trainees:

Andrea Carpenter, 2005-2008, Ph.D. 2008
Velibor Savic, 2005-2009, Ph.D. 2009
Bu Yin, 2006-2010, Ph.D. 2010
Marta Rowh, 2006-2010, Ph.D. 2010
Brenna Brady, 2007-2011, Ph.D. 2011