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Defining the role of the gut microbiome in colorectal cancer: an analysis of molecular mechanismsPrentice, Brandon 26 February 2021 (has links)
Colorectal cancer (CRC) has the 3rd highest incidence and 2nd highest mortality of all cancers in the United States. These numbers have improved with proper screening and the development of new therapies, but CRC continues to evade detection and resist therapy in late stages. The gut microbiome has emerged as a possible explanation for heterogeneity in this disease. In order to help develop screening techniques and accurate, targeted therapies, this review covers the molecular mechanisms by which the microbiome induces CRC. An analysis of current research has confirmed its physiological roles of maintaining intestinal immune homeostasis and metabolizing products produced by the host. When these functions are impaired, CRC can develop. This may occur through damage to the intestinal barrier, inflammation, and production of genotoxins and other metabolites with carcinogenic potential.
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GENOTOXIN-INDUCED ACETYLATION OF THE WERNER SYNDROME PROTEIN (WRN) AND EFFECT ON ITS DNA METABOLIC FUNCTIONLozada Santiago, Enerlyn Meliza 01 January 2011 (has links)
Loss of function of the WRN protein causes the genetic disorder Werner Syndrome that is characterized by increased cancer and premature aging. WRN belongs to the RecQ helicase family that plays key roles in preventing genome instability. In response to treatment with genotoxins, WRN is subject to post-translational modification. The relationship of post-translational modification of WRN with its function in DNA metabolism is unknown. There is accumulating evidence suggesting that WRN contributes to the maintenance of genomic integrity through its involvement in DNA replication. Consistent with this notion, WS cells are sensitive to DNA replication inhibitors and DNA damaging agents that tend to block replication fork progression. The cells exhibit an extended S phase, as well as defects in normal bi-directional progression of replication forks diverging from the majority of replication origins. To elucidate the relationship between post-translational modifications of WRN with its function in DNA metabolism, here the acetylation of WRN was studied. In our studies, we provide evidence that WRN acetylation is a dynamic process that strongly correlates to blockage of replication by persistent DNA damage. We also determined the effect of WRN acetylation on its specificity and enzymatic functions. In addition, our studies reveal how agents that block replication regulate the nature of WRN interactions with RPA, a factor known to bind to single-stranded DNA generated at blocked replication forks. Our results demonstrated that WRN and RPA form a stable direct association under normal physiological conditions and treatments that block replication fork progression increase their association, further supporting the idea that WRN is involved in DNA replication through its action at blocked or stalled replication forks. Thus, these studies point to both 1) an important role for acetylation of WRN and 2) its interaction with RPA in the putative function of WRN in response to blocked replication. Overall, our results impact knowledge regarding the relationship between DNA damage, genome instability and the development and progression of aging and cancer.
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Multiple Genotoxic Agents Activate ATR Kinase Signaling in Quiescent Human CellsMadkhali, Mariyyah Ahmed O. 18 May 2020 (has links)
No description available.
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