Metabolic Diseases Caused by Defective DNA Damage Repair

Cardiovascular disease

Heart injuries cause reduction in pumping function of heart. Heart failure has been reported to promote the accumulation of DNA damage in cardiac tissue and visceral fat which aggravates in systemic resistance in insulin and inflammation of adipose tissue. Too much lipolysis associated with sympathetic nervous system activation causes increase in oxidative stress which leads to DNA lesions and inflammation of adipose tissue through signaling of p53. Inflammation of Adipose tissue inhibits through p53 deletion can stop metabolic defects and cardiac dysfunction which indicates that a there exists a feedback loop between the fat tissue and heart. Another study has suggested an association between diabetes and vascular function. Endothelial p53 expression has noticeably upregulated when mice fed with a diet high in calories because increased DNA lesions associated with these metabolic stresses. Endothelial p53 activation leads to improvement of insulin resistance and obesity, while upregulation of endothelial p53 inhibition precipitates metabolic defects by glucose homeostasis inhibition in skeletal muscle. Such studies raised the prospect that DNA damage response inhibition in some of the different tissues could be remedial target for blocking between cardiovascular dysfunction and metabolic defective cycles.

Diabetes

Increased oxidative DNA damage levels have associations with high ROS levels found in humans and rodents with diabetes disease. High levels of 8-OH-dG are found in diabetes and obestity and reported by studies to exhibit a positive association with body mass index (BMI) of diabetic subjects. Telomeres are short endings of chromosomes which upon replication are not correctly or completely replicated, cause the activation of p53 dependent damage response. These telomeres replication complication are also linked with insulin resistance and obesity. In Diabetes type-II, it has been found that those having atherosclerotic plaques have high levels of telomeres shortening that those found in with plaques. Telomerase is an enzyme that adds telomeres to the terminals of chromosomes. Mice lacking an important enzyme for adding telomeres in chromosomes show normal phenotype during the first generation, due to having long telomeres. But, with the successive generations, their telomere gradually becomes short and reduces lifespan of such mice. They also show different types of pathology associated to age which includes a low levels of responding capabilities against stress such as hematopoietic ablation and wound healing. These mice developed insulin resistance and glucose intolerance upon feeding with a diet rich in calories without obesity development. Dysfunctional telomeres also encourage adipocytes senescence by activation of p53-dependent signals; induce systemic insulin resistance and chronic inflammation. It is also related with damaged mitochondrial functioning, reduction in gluconeogenesis, and increased ROS levels. Mechanistically, It also causes p53 activation by downregulating the coactivators (PGC)-1a and b expressions. These cofactors are actually transcriptional cofactors which change expression of different genes that perform functions in glucose and mitochondrial metabolism. Secretion of insulin is also affected in mice with telomeres of shorter length, causing glucose intolerance regardless of their normal beta cells mass. Different reports suggest that telomere shortening is associated with age and can cause the glucose homeostasis impairment by inducing inflammation in tissues, disturbing cells metabolic systems and reduction in tissue regeneration.

Ataxia Telangiectasia

Absence of DNA lesion sensor ATM (Ataxia Telangiectasia Mutated) can cause a problem known as ataxia telangiectasia (A-T). This A-T is unusual autosomal problem can be distinguish by elevated cancer incidence and ionizing radiation sensitivity, cerebellar ataxia and immune dysfunction . The lifespan for patients with this A-T is expected roughly to be around 20 years. A-T patients exhibit premature aging symptoms, insulin resistance and reduced affinity of insulin receptor. ATM deficient mouse models exhibits increase in blood glucose in age dependence manner and reduced levels of insulin sensitivity in steady-state with a evolutionary conserved metabolic role of this protein. In mouse model of ApoE-/-, haploinsufficiency of Ataxia Telangiectasia Mutated can take to high atherosclerosis levels and many metabolic syndrome features linked with ApoE-/- mouse.

Seckel syndrome

Stocked replication forks can activate Rad-related protein and ataxia telangiectasia which causes the activation of cell cycle checkpoints. Any problem in human ATR signaling can lead to Seckel syndrome; distinguishing by severe microcephaly and growth retardation (90). While secretion of growth hormone remains normal, this Seckel syndrome can be detected by high levels of circulating IGF-1 and slightly reduced levels of IGF-1 receptor binding affinity. Either this shows a constitutive problem in signaling of IGF-1 or in adaptive response for a problematic DNA lesions response is still unknown.

Tumor suppressor p53

Tumor suppressor gene p53 activation due to stress or genotoxicity can cause different results that can decrease the chance of a cell lesion making progress into a tumorous cell, varies from cell senescence to apoptosis. in addition to its function in reaction to genotoxic stress, this p53 acting a vital role in cell energy metabolism by regulating  process of oxidative phosphorylation, fatty acid synthase  and glucose transporter expression. In a Mice with defected p53 engineered, are extremely prone to cancer, also exhibit a variety of metabolic phenotypic signs and symptoms. For instance, p53 phosphorylation at Ser18 by ATM regulates glucose homeostasis. S18A mutation makes insulin resistant mice (94). Gene p53 triggered in adipose tissues on high fat containing diet by inducing insulin resistance and obesity in mice; p53 inhibition in adipose tissue set free senescence and resistance to diabetes in diabetic mice. As a whole, data suggests that activation of p53 via oxidative stress due to DNA lesions and over-nutrition can cause metabolic syndrome.

DNA-PK, KU

Ku70, Ku80 and DNA-PK make a complex molecule at double stranded breaks to assist nonhomologous end joining also called NHEJ. Mice lacking the DNA-PK catalytic subunit DNAPKcs reveal speed up aging, growth problems and decrease in lifetime. Mice that lacks Ku80 shows premature aging indication which includes hepatocellular degeneration, skin, age-specific mortality, osteopenia, and atrophic; Ku70-/- mice exhibit growth retardation. High levels of  lymphoma and defects in T and B cells of Ku70, Ku80 and DNA-PK mice are recognized by lack of NHEJ which results in lack of V(D)J recombination essential for adaptive resistance; though, premature aging phenotypic signs are not visible in Rag1 (V(D)J deficient) mice. So it may not link to deficiency of adaptive immunity and related inflammation. Decrease in Ku80 mice size is not a reason of decreased levels of IGF-1. Instead it might be related to deficiency in cell self-directed proliferation.

Deficiency of NEIL1 DNA glycosylase

NEIL1 glycoslyase starts repairing of oxidative damages in BER pathways by specifically acting  on 4,6-diamino-5-formamidopyrimidine and 2,6-diamino-4-hydroxy-5-formamidopyrimidine damaged sites. NEIL-1 glycosylase deficient mouse model developed severe dyslipidemia, hyperinsulinemia, obesity and fatty liver disease in the deficiency of exogenous oxidation stress. In NEIL1-/- mice, the onset of metabolic syndrome is speed up on a high fat containing diet which indicates that NEIL1 absence make mice more vulnerable to oxidative stress make metabolic syndrome.

SIRT6

Yeast SIR2 have a homoluge in mammals, called SIRT6 that is NAD-dependent enzyme known as histone deacetylase. Initially SIRT6 was described as a BER system component, as these SIRT6 lacking MEFs are highly sensitive to BER-damage causing agents such as hydrogen peroxide and methyl methanesulfonate; sensitivity was re-establish to that of natural form by introducing Polβ dRP lyase domain. Though there were no direct contact between BER factors and SIRT6, SIRT6 appeared to effecting DNA damage repair through maintaining the chromatin and helping DNA-PK dependent signaling lesions. This SIRT6 have been found to affect metabolic process both through lysine 9 of histone H3 deacetylation and by inhibiting HIF1 to regulate or maintain the glycolytic genes expression, which describes the glucose imbalance that can be in seen SIRT6 knockout mice. Like Hutchinson-Gilford syndrome NER system, in mice knocked out of SIRT6 have decreased levels of serum IGF-1, causes their small size. Neural removal of SIRT6 neuraly cannot protect the failure of postnatal growth, but it can protect the severe conditions of hypoglycemia, leading to full body deaths due to SIRT6 knock outs.

Werner syndrome

Werner syndrome (WS) can be identified by short height, loss and early grayish hair. There exists no such proof for deficiency in endocrine as an clarification for deficiency in growth.  Diabetes mellitus type-2 and dyslipidemia causes atherosclerosis that are common characteristics of WS. Werner syndrome patient usually survive into their mid-50s age and die due to premature disease of cancer or cardiovascular. WS patients also exhibit high accumulations of brain amyloid Beta peptides and high phosphorylated tau, both problems are mostly common in disorders associated with age. WS is also linked with myelin fibers loss, both in the peripheral and central nervous system  without delaying in neuronal expansion as observed in central nervous system. Defect in a Rec-Q helicase causes WS. This REC-Q helicase is responsible in hydrolyzing ATP for separation of dsDNA for recombination, replication, repair and transcription. The REC-Q helicase is crucial for the maintainence of chromosomal integrity by whole DNA replication or recombination. Many features of Werner syndrome are faithfully recapitulated in a mouse model in which the WRN gene is lacking the helicase domain. Helicase domain lacking mice have increased ROS levels and DNA damage due to oxidation in heart and liver, and increased levels of serum triglycerides, insulin and glucose; all of them upon treating with a long duration of vitamin C returned to wild types. WRN emerges to have an important role in cells protection from oxidative lesions this WRN loss can lead to alterations similar to metabolic syndrome.

Other Diseases Associated with DNA Damage

Alzheimer’s disease, Parkinson’s disease, Acute lymphoblastic leukemia, Hematological disorders, Multiple sclerosis, breast cancer, Colorectal cancer, Invasive ductal carcinoma, Friedreich ataxia, Amyotrophic lateral Sclerosis, Gynecological cancers, Cervical cancer, Renal cell carcinoma, Haemochromotosis, Wilson’s disease, Chronic hepatitis, Cystic fibrosis, Lung cancer, Atopic dermatitis, Psoriasis, Gastric adenocarcinoma, Gastric cancer, Assorted cancers, Fanconi’s anemi, Rheumatoid arthritis,  Systemic lupus erythematosus.