Paolo Casali
Medicine, Molecular Biology & Biochemistry, Center for Immunology
School of Medicine
Phone: (949) 824-9648
Email: pcasali@uci.edu
http://casalilab.bio.uci.edu/
http://www.faculty.uci.edu/profile.cfm?faculty_id=4943
Paolo Casali
Dr. Paolo Casali wants to understand the mechanisms that underlie the generation of class-switched and high affinity (hypermutated) antibodies to microbial antigens, self-antigens and tumoral antigens. Such mechanisms unfold through a B-lymphocyte coordinated differentiation program, in general, in the germinal center of peripheral lymphoid organs. Dr Casali continues to combine genetic, biochemical and cell biology methodologies to address the mechanisms that underlie immunoglobulin (Ig) somatic hypermutation (SHM) and class switch DNA recombination (CSR), and the regulation of these processes. While SHM and CSR are critical for the generation of high affinity class-switched antibodies that fight bacterial and viral infections, and control the emergence and the growth of many tumors, these processes have the potential to profoundly perturb the homeostasis of the genome by effecting specific DNA lesions, including DNA cleavage and double strand DNA breaks (DSBs). Dr. Casali argues that in mature B cells the expression of the initiator of such DNA lesions, activation-induced cytidine deaminase (AID), is tightly regulated and so is its targeting to Ig V(D)J and switch (S) region DNA. He contends that the resolution of AID-mediated lesions is effected by lesion-bypass or translesion DNA synthesius (TLS) polymerases while repairing DNA outside main DNA replication, resulting in the introduction of mismatches, i.e., mutations, as found in Ig V(D)J genes and recombined S-S region sequences. By utilizing human B cells and mice that are deficient in DNA repair proteins, transcription regulation factors and/or TLS polymerases, Dr. Casali has shown AID plays an important post-cleavage role in the generation of staggered DSBs in S regions and has identified polymerase θ as a major TLS in the DNA repair process that leads to insertion of mutations. Further, he is now testing the hypotheses that the family of 14-3-3 adaptor proteins play a critical role in CSR by targeting relevant transcription factors and mismatch repair proteins to S regions, and that the conserved HoxC4 helix-loop-helix homeodomain protein critically regulates AID expression and the transcription of the Ig heavy chain locus. Dr. Casali hopes that the elucidation of the DNA lesions, the repair processes and the Ig locus transcriptional regulation involved in SHM and CSR will eventually unveil the precise mechanisms that underlie the maturation of the specific antibody response. Dysregulation of such mechanisms would lead to defective immunoresponses, impaired microbial and tumoral cell clearance as well as important genetics defects, including chromosomal translocation and dysregulation of oncogene expression, thereby promoting chronic infections, neoplastic transformation and cancer.
Current experiments use in vitro B cell lines and newly generated polymerase and mismatch repair (MMR) protein knock-out mice to address the role of newly identified DNA polymerases, DNA-binding factors and MMR proteins in the repair process of DSB in Ig V(D)J and S DNA as well the role of yet to be identified endonucleases involved in the generation of those DNA lesions. The role of the phylogenetically conserved HoxC4 homeodomain protein in the transcription regulation of the IgH locus and modulation of CSR and SHM is being addressed using HoxC4 -/- mice we have recently generated at UCI.
Selected Publications:
Xu, Z., Pone, E. J., Al-Qahtani, A., Park, S. R., Zan, H., and Casali, P. (2007). Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination. Crit Rev Immunol 27(4), 367-97.
Xu, Z., Zan, H., Pal, Z., and Casali, P. (2007). DNA replication to aid somatic hypermutation. Adv Exp Med Biol 596, 111-27.
Atassi, M. Z., and Casali, P. (2008). Molecular mechanisms of autoimmunity. Autoimmunity 41(2), 123-32. |
