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DNA Damage Response Research, Inherent and Future Nano-Based Interfaces for Personalized Medicine
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Madhu Dyavaiah, Lauren Endres, Yiching Hsieh, William Towns, Thomas J. Begley
In addition to the MRN and 9-1-1 complexes, two poly ADP-ribose polymerase (PARP) family members, PARP1 and PARP2, are also known to be molecular sensors of both single-strand and double-strand DNA breaks. Mouse cells deficient in Parp1 or Parp2 display delayed single-strand break repair and hypersensitivity to ionizing radiation (Yelamos et al. 2008). Activation of PARP1 and PARP2 by strand breaks immediately triggers the synthesis of poly ADP-ribose chains that recruit DDR proteins to the damage site. PARP1 and PARP2 targets include histones and DNA-repair proteins, among others, to promote repair. Both PARP1 and PARP2 also interact with a number of single-strand break- and base excision-repair proteins (X-ray repair cross-complementing protein 1 [XRCC1], DNA polymerase β, and DNA ligase III), which are thought to stimulate activities in each of their respective repair pathways. PARP1 also mediates the accumulation of the MRN complex on DNA lesions to facilitate ATM activation and signaling (Haince et al. 2007, 2008). However, ATM and PARP1/PARP2 have independent functions in the DNA damage response pathway due to the synthetic lethality of PARP1/PARP2 deletion in the ATM deficiency mouse model (Huber et al. 2004). The heart of PARP1 and PARP2’s activity is the synthesis of poly ADP-ribose chains using NAD+ to catalyze the addition of ADP-ribose to a growing chain, with this activity being stimulated upon binding of strand breaks. The structure of PARP1 in complex with a DNA-double-strand break has recently been determined, and damage identification was found to occur through a sequence-independent mode of action (Langelier et al. 2011). PARP1 uses a phosphate backbone grip and a base-stacking loop to interact with the phosphate backbone and expose nucleotides found at the double-strand break. The phosphate backbone grip is envisioned to bind ∼1 nm of uninterrupted DNA (three nucleotides) with the base-stacking loop being a flexible component that allows for interaction with a range of DNA structures found at the end of damaged DNA strands. Analysis of PARP1 structures in the absence or presence of DNA suggests that the base stacking loop will reposition itself ∼1 nm, away from the main structure to facilitate interaction with nucleotides. Structural data on PARP1 thus highlights important nanoscale features used for damage recognition.
Genotoxicity biomarkers in car repair workers from Barranquilla, a Colombian Caribbean City
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Jaime Luna-Carrascal, Milton Quintana-Sosa, Jesus Olivero-Verbel
Although the frequencies in the heterozygotes were higher in the exposed group, some of these genes, especially XRCC1, might be exerting an important repair effect in exposed individuals. The XRCC1 was shown to play an important role in repairing DNA damage and adducts (Cui et al. 2012). This process is accompanied by the action of the OGG1 gene that catalyzes cleavage of oxidized purines, such as 8-oxo-7,8-dihydroguanine and its ring-opened derivatives (Moritz et al. 2014; Rohr et al. 2011). Further, the major polymorphism in the human OGG1 gene leads to the substitution of cysteine for serine, which may reduce repair efficiency of the enzyme (Kershaw and Hodges 2012). In fact, such substitutions increase risk of several types of cancer (Kang et al. 2017) and may explain the higher frequency of individuals with OGG1 326 Ser/Cys genotypes compared to OGG1 326 Ser/Ser carriers. Further, both GSTT1 and GSTM1 are involved in the metabolism of numerous carcinogens and reactive oxygen species (ROS) (Kadioglu 2016; Singh et al. 2012), although their expression may vary between individuals. In this study, the presence of individuals with a null genotype was observed, indicating the respective enzymes are not present in homozygous individuals (Kadıoğlu et al. 2016); in addition, the GSTT1 variant is directly associated with enhanced DNA damage and adduct formation (Sram et al. 2007), or may display an attenuated response (Kim et al. 2002). In the case of the GSTM1 gene, the null variant might be related to health susceptibilities mediated by air pollutants (Bowatte et al. 2016; Chiu et al. 2016), thus able to modulate proinflammatory expression capacity (Chahine et al. 2007; Madrigano et al. 2010) and cell adhesion (Rückerl et al. 2014; Wu et al. 2012; Yang et al. 2008). Therefore, these individuals cannot conjugate specific metabolites, increasing the potential for oxidative damage and related conditions, such as lung diseases (Minina etal. ; Sharma et al. 2015).