DELINEATING THE ROLE OF THE HOMOCYSTEINE-FOLATE-THYMIDYLATE SYNTHASE AXIS AND URACIL ACCUMULATION IN AFRICAN AMERICAN PROSTATE TUMORS

众所周知，非裔美国人前列腺癌患者被诊断出的年龄较早，具有侵袭性。 罹患前列腺癌的几率是其他人口群体的两倍。尽管有一次重大的 关注社会经济因素，最近的发现有力地证明了生物因素的存在 癌症差异。在我努力了解前列腺癌的生物驱动因素时，我应用了一种新的DNA 损害检测方法，修复辅助损害检测(RADD)，并建立了非裔美国人 总体上，肿瘤的DNA损伤比EA肿瘤多，尤其是尿嘧啶损伤。我们的实验室之前 证明同型半胱氨酸-蛋氨酸途径是非裔美国人前列腺癌的代谢标志 癌症，它促进了脱氧尿苷转化所需的叶酸循环的进展 单磷酸(DUMP)到脱氧胸苷单磷酸(DTMP)。糖尿病患者体内代谢物的上调 在非洲发现了新的嘧啶生物合成途径和叶酸循环代谢物的变化水平 美国前列腺癌，提示尿嘧啶代谢和尿嘧啶病变累积之间的联系。尿嘧啶 损伤通过碱基切除修复途径修复。我们还展示了XRCC1、a 参与协调碱基切除修复功能的蛋白质在非裔美国人前列腺癌中较低， 表明有缺陷的碱基切除修复。这些数据共同表明，非裔美国人的肿瘤表现出 胸苷应激的后果，其中胸苷合成酶(TYMS)将转储转化为 DTMP受阻，通过保留尿嘧啶损伤，导致碱基切除的调节失调。这个 非裔美国人男性尿嘧啶皮损的增加可能是由于 核苷酸代谢，这是由叶酸循环和一碳一碳的成分水平变化引起的 新陈代谢。众所周知，这些成分，如维生素B12和叶酸，在非裔美国人中会减少 男性，这可能是由于饮食不足或由于同型半胱氨酸-蛋氨酸循环异常所致， 或者两者都有。虽然我们了解叶酸减少的分子后果，因为它与尿嘧啶积累有关， 围绕着通过调节维生素B12和叶酸的DNA损伤反应的情况是 目前尚不清楚。这项提议的假设是，维生素B12和叶酸水平的变化有助于 胸苷应激导致碱基切除修复途径功能障碍并促进前列腺癌 非裔美国人男性的进步。在这项提案中，我们将1)确定 同型半胱氨酸、维生素B12和叶酸与非裔美国男性前列腺癌进展 阐明同型半胱氨酸、维生素B12和叶酸对Tyms功能和碱基切除的调节作用 非裔美国人前列腺癌患者的修复。成功完成这些目标将建立起一种联系 非裔美国男性前列腺癌患者的代谢和DNA修复之间的关系，并有助于新陈代谢的发展 对这些患者进行DNA修复抑制剂治疗的生物标记物进行分层。

African American prostate cancer patients are known to be diagnosed at an earlier age, present with aggressive disease, and are twice as likely to succumb to prostate cancer than other demographic groups. Despite a major focus on socioeconomic factors, recent findings strongly argue for the existence of biological factors driving cancer disparities. In my efforts to understand biological drivers in prostate cancer, I applied a novel DNA damage detection method, Repair Assisted Damage Detection (RADD), and established that African American tumors have more DNA lesions overall than EA tumors, especially uracil lesions. Our lab has previously demonstrated that the homocysteine-methionine pathway is a metabolic hallmark of African American prostate cancers, which fuels the progression of the folate cycle that is required for the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). An upregulation of metabolites in the de novo pyrimidine biosynthesis pathway and altered levels of folate cycle metabolites were identified in African American prostate tumors, suggesting the link between uracil metabolism and uracil lesion accumulation. Uracil lesions are repaired by the base excision repair pathway. We have also shown that expression of XRCC1, a protein involved in coordinating base excision repair function, was lower in African American prostate tumors, indicative of defective base excision repair. These data collectively suggest that African American tumors exhibit the consequences of thymidylate stress, where the ability of thymidylate synthase (TYMS) to convert dUMP to dTMP is obstructed, resulting in dysregulation of base excision through the retention of uracil lesions. The increased amounts of uracil lesions in African American men could be a cumulative result of changes in nucleotide metabolism, which is caused by altered levels of components in the folate cycle and one-carbon metabolism. These components, such Vitamin B12 and folate, are known to be reduced in African American men, which could result from either dietary deficiencies or due to an aberrant homocysteine-methionine cycle, or both. While we understand the molecular consequences of reduced folate as it relates to uracil accumulation, the circumstances surrounding the DNA damage response through the regulation of Vitamin B12 and folate is currently unknown. The hypothesis of this proposal is that altered levels of Vitamin B12 and folate contribute to thymidylate stress, resulting in base excision repair pathway dysfunction and promoting prostate cancer progression in African American men. In this proposal, we will 1) determine the clinical relevance of homocysteine, Vitamin B12, and folate with prostate cancer progression in African American men and 2) elucidate the role of homocysteine, Vitamin B12, and folate regulation on TYMS function and base excision repair in African American prostate cancer patients. Successful completion of these aims will establish a link between metabolism and DNA repair in African American men with prostate cancer and help develop metabolic biomarkers to stratify these patients for DNA repair inhibitor therapies.