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DNA repair and brain health

DNA damage and repair
The genetic material in every living organism is constantly challenged by endogenous and exogenous DNA damaging agents. To maintain the integrity of DNA, cells have evolved well-conserved DNA repair pathways. The DNA repair pathways interact with a network of pathways that work together ensure that cells respond in a coordinated manner to DNA damage, collectively termed as DNA damage response (DDR).

There are two fundamentally different mechanisms of DNA repair: direct reversal of damage or excision of damage. Direct reversal is the simplest form of repair where proteins have evolved to remove specific modifications without excision of the base and new synthesis of DNA. One example is O6-methylguanine DNA methyltransferase (MGMT). The bulk of DNA damage is removed by excision-repair mechanisms, where a damaged base or nucleotide is removed and replaced by new synthesis of DNA. There is a large variety of chemical modifications to DNA that is dealt with using different biochemical strategies and enzyme systems that constitute DNA repair pathways: Nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination (HR), and nonhomologous end joining (NHEJ). NER is the most versatile repair pathways and is dedicated to repairing covalent, helix-distorting lesions. Classical NER lesions include the UV-induced cyclobutane pyrimidine dimers (CPDs) and 6-4-photoproducts. MMR corrects base-base mismatches and insertion deletion loops caused during DNA replication. HR and NHEJ repair DNA double strand breaks (see (Keijzers et al., 2017) for a nice graphical overview of repair pathways).

The BER pathway is the primary pathway for repair of oxidized bases, hydrolytic deamination products (uracil, AP-sites), alkylated bases, and single strand breaks (Barnes and Lindahl, 2004). The first step of BER involves recognition of lesion by damage-specific DNA glycosylases (Jacobs and Schar, 2012). In mammals there are 11 DNA glycosylases that, together, can deal with the products formed by endogenous DNA damaging agents. This strategy is different from both NER and MMR, which use one or two lesion recognition strategies.

Humans with DNA repair defects often develop severe neurological diseases
Defects in any of these DNA repair pathways results in human disease (Keijzers et al., 2017). The spectrum of pathology is wide and ranges from severe developmental abnormalities to relatively mild diseases. One group of DNA repair diseases clearly shows an interesting, progressive phenotype that resembles some, but usually not all aspects of aging - a phenotype summed up by the term ‘segmental progeria' (or ‘early-aging'). Cells and animal models (see text box) of these segmental progerias have been very informative and have taught us that defects in DNA repair can drive aging.

Werner syndrome (WS), caused by mutation in the WRN gene, is the best example of a DNA repair disease that resembles normal aging. In WS there are no cognitive or developmental defects, but agingrelated symptoms appear at a much higher rate: in their 30s patients already have an appearance associated with old age - such as graying hair, skin atrophy and loss of subcutaneous fa
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NBS-nytt 14.02.2021
Det første NBS kontaktmøtet fant sted i 1964, og ideen var hvert år å samle det biokjemiske miljøet i Norge i en atmosfære som ikke bare inkluderte det faglige, men også det sosiale!
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NBS-nytt 14.02.2021
Det norske bioteknologiselskapet Vaccibody går så det griner. Hva driver de med?
NBS-nytt 14.02.2021
Som eldre lesere av NBS-nytt vil vite, har en av Biorabiatens viktigste samfunnsoppgaver i en årrekke vært å fungere som et korrektiv til Norges forskningsråd.
NBS-nytt 14.02.2021

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