The long-term objectives of this application are to better understand the DNA damage mechanisms that influence the response of normal cells and cancer cells to chemotherapy. Thymidylate deprivation is induced by inhibition of thymidylate synthase (TS) and is a therapeutic effect of several classes of antineoplastic drugs, such as 5-fluorouracil and raltitrexed (Tomudex). Inhibition of TS leads to loss of TTP necessary for replication. Thymidylate deprivation leads to cell death, unlike the cytostatic effects associated with other nutritional deficiencies. Despite decades of study, the precise mechanism by which TS inhibition causes death remains unclear. Some cellular responses to TS inhibition include an alteration in deoxynucleotide pools including an increase in dUTP levels, uracil incorporation into DNA, cell cycle arrest during S-phase, and induction of DNA strand breaks, likely at sites of replication. A key unanswered question remains """"""""what is the specific nature of the damage during thymidylate deprivation that results in cell death?"""""""" The hypothesis to be tested in this project is that activation and progression of base excision repair (BER) under conditions of thymidylate deprivation lead to aberrant recombination and, eventually, apoptosis.
The Specific Aims of this project are:
Aim 1 : To determine whether the initiation and progression of BER during thymidylate deprivation contributes to cell death.
Aim 2 : To determine the fate of BER intermediates during thymidylate deprivation.
Aim 3 : To determine whether chromosomal recombination is induced during thymidylate deprivation and to investigate the influence of BER on recombination occurring during thymidylate deprivation. Because BER and recombination normally contribute to genome stability, these questions have an added significance when current cancer therapies can themselves induce DNA damage.
|Wyatt, Michael D; Reilly, Nicole M; Patel, Shikha et al. (2018) Thiopurine-induced mitotic catastrophe in Rad51d-deficient mammalian cells. Environ Mol Mutagen 59:38-48|
|Das, Dipon; Preet, Ranjan; Mohapatra, Purusottam et al. (2014) 5-Fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of Adenomatous Polyposis Coli: Implication of the long-patch base excision repair pathway. DNA Repair (Amst) 24:15-25|
|Nagaria, Pratik; Svilar, David; Brown, Ashley R et al. (2013) SMUG1 but not UNG DNA glycosylase contributes to the cellular response to recovery from 5-fluorouracil induced replication stress. Mutat Res 743-744:26-32|
|Yang, Zhengguan; Waldman, Alan S; Wyatt, Michael D (2012) Expression and regulation of RAD51 mediate cellular responses to chemotherapeutics. Biochem Pharmacol 83:741-6|
|Hampson, Richard J; Wyatt, Michael D (2011) Whole organism based techniques and approaches in early stage oncology drug discovery-patents and trends. Recent Pat Endocr Metab Immune Drug Discov 5:183-91|
|Rajesh, Preeti; Litvinchuk, Alexandra V; Pittman, Douglas L et al. (2011) The homologous recombination protein RAD51D mediates the processing of 6-thioguanine lesions downstream of mismatch repair. Mol Cancer Res 9:206-14|
|Rajesh, Preeti; Rajesh, Changanamkandath; Wyatt, Michael D et al. (2010) RAD51D protects against MLH1-dependent cytotoxic responses to O(6)-methylguanine. DNA Repair (Amst) 9:458-67|
|Jones Jr, Larry E; Ying, Lei; Hofseth, Anne B et al. (2009) Differential effects of reactive nitrogen species on DNA base excision repair initiated by the alkyladenine DNA glycosylase. Carcinogenesis 30:2123-9|
|Wyatt, M D; Wilson 3rd, D M (2009) Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci 66:788-99|
|Waldman, Barbara Criscuolo; Wang, Yibin; Kilaru, Kasturi et al. (2008) Induction of intrachromosomal homologous recombination in human cells by raltitrexed, an inhibitor of thymidylate synthase. DNA Repair (Amst) 7:1624-35|
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