Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto, Japan.
Published: March 2012
AI Article Synopsis
Article Abstract
ATR kinase activates the S-phase checkpoint when replication forks stall at sites of DNA damage. This event also causes phosphorylation of the Fanconi anemia (FA) protein FANCI, triggering its monoubiquitination of the key DNA repair factor FANCD2 by the FA core E3 ligase complex, thereby promoting this central pathway of DNA repair which permits replication to be restarted. However, the interplay between ATR and the FA pathway has been unclear. In this study, we present evidence that their action is directly linked, gaining insights into this relationship in a DT40 mutant cell line that is conditionally deficient in the critical ATR-binding partner protein ATRIP. Using this system, we showed that ATRIP was crucial for DNA damage-induced FANCD2 monoubiquitination and FANCI phosphorylation. ATR kinase phosphorylated recombinant FANCI protein in vitro, which was facilitated by the presence of FANCD2. Mechanistic investigations revealed that the RPA region but not the TopBP1 region of ATRIP was required for FANCD2 monoubiquitination, whereas Chk1 phosphorylation relied upon both domains. Together, our findings identify ATR as the kinase responsible for activating the FA pathway of DNA repair.
Background: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.
Objective: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.
Streptozotocin (STZ) is widely used as a pancreatic beta-cell toxin to induce experimental diabetes in rodents. Strain-dependent variations in STZ-induced diabetes susceptibility have been reported in mice. Differences in STZ-induced diabetes susceptibility are putatively related to pancreatic beta-cell fragility via DNA damage response.
Department of Neurosciences and Mental Health, Unidade Local de Saúde de Santa Maria, Lisbon, Portugal; Faculdade de Medicina-Instituto de Medicina Molecular, Centro de Estudos Egas Moniz, Universidade de Lisboa, Lisbon, Portugal.
Objective: To present cases of ptosis in HIV-1 patients on long-term antiretroviral therapy (ART) and review the existing literature.
Methods: Five HIV-1-positive patients with slowly progressive bilateral ptosis underwent a comprehensive diagnostic evaluation, including imaging studies, neurophysiological testing, muscle biopsy, and genetic analysis. A literature review was conducted.
Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States.
DNA interstrand cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. Selenium compounds showed great potential as anticancer drugs. In this work, we synthesized a binaphthalene analog containing phenyl selenide (-SePh) as the leaving group and investigated its photochemical reactivity toward DNA as well as its cytotoxicity and selectivity.
Despite the remarkable resistance of the nucleic acid phosphodiester backbone to degradation affording genetic stability, the P-O bond must be broken during DNA repair and RNA metabolism, among many other critical cellular processes. Nucleases are powerful enzymes that can enhance the uncatalyzed rate of phosphodiester bond cleavage by up to ∼10-fold. Despite the most well accepted hydrolysis mechanism involving two metals (M to activate a water nucleophile and M to stabilize the leaving group), experimental evidence suggests that some nucleases can use a single metal to facilitate the chemical step, a controversial concept in the literature.
