Base excision repair in the mammalian brain: Implication for age related neurodegeneration

Abstract

The repair of damaged DNA is essential to maintain longevity of an organism. The brain is a matrix of different neural cell types including proliferative astrocytes and post-mitotic neurons. Post-mitotic DNA repair is a version of proliferative DNA repair, with a reduced number of available pathways and most of these attenuated. Base Excision Repair (BER) is one pathway that remains robust in neurons; it is this pathway that resolves the damage due to oxidative stress. This oxidative damage is an unavoidable byproduct of respiration, and considering the high metabolic activity of neurons this type of damage is particularly pertinent in the brain. The accumulation of oxidative DNA damage over time is a central aspect of the theory of aging and repair of such chronic damage is of the highest importance. We review research conducted in BER mouse models to clarify the role of this pathway in the neural system. The requirement for BER in proliferating cells also correlates with high levels of many of the BER enzymes in neurogenesis after DNA damage. However, the pathway is also necessary for normal neural maintenance as larger infarct volumes after ischemic stroke are seen in some glycosylase deficient animals. Further, the requirement for DNA polymerase β in post-mitotic BER is potentially more important than in proliferating cells due to reduced levels of replicative polymerases. The BER response may have particular relevance for the onset and progression of many neurodegenerative diseases associated with an increase in oxidative stress including Alzheimer’s.

Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety

“…Furthermore, model compound 2,2,2-trifluoro-N-(8-(trifluoromethyl)benzo[f] [1,2,3,4,5]pentathiepin-6-yl)acetamide (10) was made using amine 1 and (CF 3 CO) 2 O as previously described. 30 …”

“…The eleven N-(benzo[f] [1,2,3,4,5]pentathiepin-6-yl)acetamide derivatives (1, 3a-g, 8a,b and 10) dock into the binding pocket of TDP1 crystal structure with reasonable predicted affinity for all of the scoring functions used (see Table S1 in Supplementary information).…”

“…These pathologies are frequently associated with aberrations in DNA repair protein expression including their hyper expression. [1][2][3] Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for cancer and neurodegenerative therapy. 4,5 TDP1 belongs to phospholipases family of enzymes that catalyze the hydrolysis of phosphodiester bonds 6 and plays an important role in removal stalled Top1-DNA covalent complexes (Top1cc), 7 generated by DNA topoisomerase I (Top1) inhibitors, such as camptothecin and some other anticancer drugs (for review see Ref.…”

The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases

“…Oxidative DNA damage is the first activator of the DNA repair enzyme poly (ADPribose) polymerase 1 (PARP-1) -an abundant nuclear enzyme whose overactivation has been proven to be associated with the pathogenesis of numerous central nervous system disorders, such as ischemia, neuroinflammation, and neurodegenerative diseases (PeraltaLeal et al, 2009;Sykora et al, 2013;). It shares a conserved catalytic domain that by using NAD+ as a donor of ADP-ribosyl units supports mono-or poly(ADP-ribosyl) transferase activity.…”

Chromatin Modifications Associated with DNA Double-strand Breaks Repair as Potential Targets for Neurological Diseases

“…Although DSBs are the most toxic DNA lesions, other types of damage, such as single strand lesions or small chemical alterations of the bases have been linked to neurodegeneration [25,26]. These lesions, which affect only one of the strands of the double helix, are the target of other repair pathways, nucleotide excision repair (NER) and base excision repair (BER).…”