The Loss Of Genomic Uracil Homeostasis And Aid-Dependent Accumulation Of Dna Damage In B Cell Lymphomas

THE LOSS OF GENOMIC URACIL HOMEOSTASIS AND AID-DEPENDENTACCUMULATION OF DNA DAMAGE IN B CELL LYMPHOMASbySOPHIA SHALHOUTMay 2015Advisor: Dr. Ashok S. BhagwatMajor: Chemistry (Biochemistry)Degree: Doctor of PhilosophyActivation-induced deaminase (AID) is a sequence-selective DNA cytosinedeaminase that introduces uracils in immunoglobulin genes. This DNA mutator isrequired for somatic hypermutation and class switch recombinationprocessesinvolved in the affinity maturation and diversification of antibodies. AID, however,can also lead to deleterious mutations and translocations promotinglymphomagenesis. The introduction of uracils throughout the genome ofactivated B cells and the ability of UNG2 glycosylase to excise these uracils isexamined here. This interplay was also studied in cancerous B cells, with different results emerging in transformed cells versus healthy cells. Genomicuracil levels are found to remain at the same level in normal B cells stimulated to express AID. However the increase in uracils by 11to 60fold detected instimulated B cells deficient in UNG, suggests that normal B cells do accumulatehigh levels of genomic uracils. However, these uracils are efficiently andeffectively removed in UNG proficient cells, suggesting a balance or homeostasisbetween uracil creation and elimination. Interestingly, murine B cell cancer lines,