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ß-Lapachone Clusterin Mismatch Repair Double Strand Break Repair

DNA Double strand breaks (DSBs) are one of the most dangerous forms of DNA lesions which a cell can encounter. This is due the inherent oncogenic potential of the free DNA ends. These ends if left un-repaired can invade surrounding genomic material leading to chromosomal translocations and eventually cancer. Double strand breaks can be introduced by several different methods. Exogenous agents and chemotherapeutic drugs such as ionizing radiation (IR) and Cisplatin can produce DSBs. These lesions are also introduced in the cell naturally during S phase of the cell cycle when DNA synthesis has stalled and by reactions involving reactive oxygen species (ROS) that are produced during normal cellular metabolism. In special cases such as in the developing B and T cells in the immune system, DSBs are introduce into the genome as part of normal development. This occurs during V(D)J and Class switch recombination. These types of breaks are repaired by a process called Non-homologous end joining (NHEJ). The cell also has a second major method of repairing DSBs and that is homologous recombination (HR). We are currently focused on studying the NHEJ pathway of repairing DSBs. Key factors involved in this pathway include the DNA dependent protein kinase (DNA-PK), Artemis, XRCC4, DNA Ligase 4, Ku70, and Ku80. Our current focus is on a novel DNA repair factor which has been termed Ku70 Binding protein 5 (Kub5). We discovered this novel factor by it’s intrinsic ability to bind Ku70. Currently we are using yeast and tissue culture model systems to study the cellular function of Kub5 in vitro and are currently in the process of developing knock-out mouse model system to study Kub5 function in vivo

Given what is known about the factors involved in the NHEJ pathway of DNA repair, Kub5 is sure to be important cellular process’ such as DNA repair, telomere maintenance and cellular senescence, immunological development, and tumor suppression.

Lab members involved in this project include Amy Rommel (Graduate Student), Tomoyuki Mashimo (Research Assocaite) and Julio C. Morales (Post-doctoral Fellow).

Immunoflourescence using Kub5 specific antibody reveals a discrete nuclear staining pattern.

University of Texas Southwestern Medical Center at Dallas - Simmons Comprehensive Cancer Center