Molecular and genetic influence of HMGA1 proteins on nucleotide excision repair.

摘要

The family of architectural transcription factors known as the high mobility group (HMG) A1 proteins are both positive and negative gene regulators that bind to DNA and chromatin substrates in a structure-specific manner. It has previously been demonstrated that over expression of HMGA1 is a naturally occurring phenotype of many cancers. It has also been shown that over expression of transgenic HMGA1 proteins promotes neoplastic transformation and progression to malignant phenotypes. The following thesis describes the effects of HMGA1 over expression on functional nucleotide excision repair (NER) pathways, providing a potential link between HMGA1 abundance and the observed genetic instability of many human cancers. Specifically, evidence that over expression of HMGA1 proteins (1) decreases overall NER efficiency and (2) disrupts coordinate transcriptional regulation of genes involved in NER is described. In addition, the following thesis will describe preliminary evidence indicating that HMGA1 proteins also compromise base excision repair (BER) pathways. As NER and BER comprise the major cellular mechanisms by which genomic integrity is maintained, these results implicate HMGA1 proteins as a target for adjuvant chemotherapy in the treatment of cancer.