Rare hereditary diseases with defects in DNA-repair.

The human genome is constantly exposed to various sources of DNA damage. Ineffective protection from this damage leads to genetic instability which can ultimately give rise to somatic disease, causing mutations. Therefore our organism commands a number of highly conserved and effective mechanisms responsible for DNA repair. If these repair mechanisms are defective due to germline mutations in relevant genes, rare diseases with DNA repair deficiencies can arise. Today, a limited number of rare hereditary diseases characterized by genetic defects of DNA repair mechanisms is known, comprising ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy. Although heterogeneous in respect to selected symptoms, these rare disorders share many clinical features such as growth retardation, neurological disorders, premature ageing, skin alterations including abnormal pigmentation, telangiectasia, xerosis cutis, pathological wound healing as well as an increased risk of developing different types of cancer. Based on the clinical similarities of symptoms as well as the predominant diagnostic technology available, many of these rare disorders were formerly classified as genodermatoses with cancer predisposition or chromosomal breakage symptoms. These pathological conditions not only severely impair patients with these rare genetic diseases but also represent symptoms affecting large parts of the general population.

Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging.

Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csb(m/m) and Csa(-/-) mice. Thus, the NER-proteins CSA and CSB localize to mt and directly interact with BER-associated human mitochondrial 8-oxoguanine glycosylase-1 to protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging found in animal models, human progeroid syndromes like CS and in normal human aging.