Medical Toxicology Commons^™

Polyubiquitination Of Apurinic/Apyrimidinic Endonuclease 1 By Parkin, Timothy L. Scott, Christina A. Wicker, Rangaswamy Suganya, Bithika Dhar, Thomas A. Pittman, Craig Horbinski, Tadahide Izumi

Toxicology and Cancer Biology Faculty Publications

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein crucial for repair of oxidized DNA damage not only in genomic DNA but also in mitochondrial DNA. Parkin, a tumor suppressor and Parkinson's disease (PD) associated gene, is an E3 ubiquitin ligase crucial for mitophagy. Although DNA damage is known to induce mitochondrial stress, Parkin's role in regulating DNA repair proteins has not been elucidated. In this study, we examined the possibility of Parkin‐dependent ubiquitination of APE1. Ectopically expressed APE1 was degraded by Parkin and PINK1 via polyubiquitination in mouse embryonic fibroblast cells. PD‐causing mutations in Parkin and PINK1 abrogated APE1 ubiquitination. …

Exposure Of Human Lung Cells To Tobacco Smoke Condensate Inhibits The Nucleotide Excision Repair Pathway, Nathaniel C. Holcomb, Mamta Goswami, Sung Gu Han, Samuel Clark, David K. Orren, C. Gary Gairola, Isabel Mellon

Toxicology and Cancer Biology Faculty Publications

Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER) pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC), a surrogate for tobacco smoke, …

Ubiquitin-Specific Peptidase 10 (Usp10) Deubiquitinates And Stabilizes Muts Homolog 2 (Msh2) To Regulate Cellular Sensitivity To Dna Damage, Mu Zhang, Chen Hu, Dan Tong, Shengyan Xiang, Kendra Williams, Wenlong Bai, Guo-Min Li, Gerold Bepler, Xiaohong Zhang

Toxicology and Cancer Biology Faculty Publications

MSH2 is a key DNA mismatch repair protein, which plays an important role in genomic stability. In addition to its DNA repair function, MSH2 serves as a sensor for DNA base analogs-provoked DNA replication errors and binds to various DNA damage-induced adducts to trigger cell cycle arrest or apoptosis. Loss or depletion of MSH2 from cells renders resistance to certain DNA-damaging agents. Therefore, the level of MSH2 determines DNA damage response. Previous studies showed that the level of MSH2 protein is modulated by the ubiquitin-proteasome pathway, and histone deacetylase 6 (HDAC6) serves as an ubiquitin E3 ligase. However, the deubiquitinating …

The Nobel Prize In Chemistry 2015: Exciting Discoveries In Dna Repair By Aziz Sancar, David K. Orren

Toxicology and Cancer Biology Faculty Publications

On October 7, 2015, the Nobel Prize in Chemistry for 2015 was awarded to three deserving scientists for their pioneering research on DNA repair. Tomas Lindahl was recognized for studies that uncovered the inherent instability of DNA as well as the mechanism of the base excision repair pathway, Paul Modrich for characterization of the mismatch repair pathway, and Aziz Sancar for mechanistic elucidation of the nucleotide excision repair (NER) pathway. For me, the announcement of these awards in my area of research was extremely gratifying, particularly so because Aziz was my mentor during my Ph.D. studies that examined the steps …

The C-Terminal Domain (Ctd) Of Human Dna Glycosylaseneil1 Is Required For Forming Berosome Repair Complex With Dna Replication Proteins At The Replicating Genome: Dominant Negative Function Of The Ctd, Pavana M. Hegde, Arijit Dutta, Shiladitya Sengupta, Joy Mitra, Sanjay Adhikari, Alan E. Tomkinson, Guo-Min Li, Istvan Boldogh, Tapas K. Hazra, Sankar Mitra, Muralidhar L. Hegde

Toxicology and Cancer Biology Faculty Publications

The human DNA glycosylase NEIL1 was recently demonstrated to initiate prereplicative base excision repair (BER) of oxidized bases in the replicating genome, thus preventing mutagenic replication. A significant fraction of NEIL1 in cells is present in large cellular complexes containing DNA replication and other repair proteins, as shown by gel filtration. However, how the interaction of NEIL1 affects its recruitment to the replication site for prereplicative repair was not investigated. Here, we show that NEIL1 binarily interacts with the proliferating cell nuclear antigen clamp loader replication factor C, DNA polymerase δ, and DNA ligase I in the absence of DNA …

Truncating Mutation In The Autophagy Gene Uvrag Confers Oncogenic Properties And Chemosensitivity In Colorectal Cancers, Shanshan He, Zhen Zhao, Yongfei Yang, Douglas O'Connell, Xiaowei Zhang, Soohwan Oh, Binyun Ma, Joo-Hyung Lee, Tian Zhang, Bino Varghese, Janae Yip, Sara Dolatshahi Pirooz, Ming Li, Yong Zhang, Guo-Min Li, Sue Ellen Martin, Keigo Machida, Chengyu Liang

Toxicology and Cancer Biology Faculty Publications

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG^FS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG^FS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG^FS can …

Acetylation Of Wrn Protein Regulates Its Stability By Inhibiting Ubiquitination, Kai Li, Rui Wang, Enerlyn Lozada, Wei Fan, David K. Orren, Jianyuan Luo

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: WRN is a multi-functional protein involving DNA replication, recombination and repair. WRN acetylation has been demonstrated playing an important role in response to DNA damage. We previously found that WRN acetylation can regulate its enzymatic activities and nuclear distribution.

METHODOLOGY/PRINCIPAL FINDING: Here, we investigated the factors involved in WRN acetylation and found that CBP and p300 are the only major acetyltransferases for WRN acetylation. We further identified 6 lysine residues in WRN that are subject to acetylation. Interestingly, WRN acetylation can increase its protein stability. SIRT1-mediated deacetylation of WRN reverses this effect. CBP dramatically increases the half-life of wild …