Role of RAD6 a DNA Repair Gene in Tumor Progression and Drug Resistance
Abstract
The goal of this IDEA award was t9 understand the role of Rad6B, a key mediator of postreplication DNA repair (PRR), in breast tumor progression and drug resistance. Results of our study demonstrated that Rad6B plays a critical role in maintenance of genomic integrity of human breast cells, as imbalances in Rad6B levels induced by experimental manipulation (and observed in human breast tumors) cause loss of cell polarity and genomic instability which correlate with alterations in chemosensitivity and PRR capacities. Rad6B forms supramolecular complexes with p53, pl4ARF and Mdm2, and inclusion of pl4ARF and M%m2 into Rad6-p53 complexes is dependent upon exposure to DNA damaging agent. Recombinant Rad6B mediates monoubiquitination of p53. That monoubiquitinated p53 functions in DNA damage-induced response is evident as G2/M arrest and p53 response observed in normal MCFlOA breast cells following DNA damage is associated with parallel increases in monoubiquitinated p53. Loss of cell polarity induced by Rad6B overexpression appears to be a result of dysregulation in Wnt and Rho signaling pathways. Samples accrued from patients post-chemotherapy shows differential distribution of Rad6 in cytoplasmic versus nuclear compartments, and our preliminary data suggest that recruitment of Rad6 into nucleus following chemotherapy may predict favorable treatment outcome.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA420380
Entities
People
- Malathy P. Shekhar
Organizations
- Wayne State University