Impact of Single Nucleotide Polymorphisms of Base Excision Repair Genes on DNA Damage and Efficiency of DNA Repair in Recurrent Depression Disorder

Czarny, Piotr; Kwiatkowski, Dominik; Toma, Monika; Kubiak, Joanna; Śliwińska, Agnieszka; Talarowska, Monika; Szemraj, Janusz; Maes, Michaël; Gałecki, Piotr; Śliwiński, Tomasz

doi:10.1007/s12035-016-9971-6

Cited by 35 publications

(22 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PARP1 is responsible for posttranslational modification of nuclear proteins in response to various types of DNA damage as well as oxidative stress (Muiras et al, 1998;Beneke and Bürkle, 2007). With an essential role in base excision repair (BER) and double strand break (DSB) repair, PARP1 has been known as the "sensor of nicks" within DNA (Mao et al, 2011;Czarny et al, 2017). Comparative studies among 13 mammalian species found that the enzymatic activity of PARP1 positively correlates with maximum lifespan in various mammals, including humans (Bürkle et al, 1992;Muiras et al, 1998;Piskunova et al, 2008;Noren Hooten et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Exonic Variants in Aging-Related Genes Are Predictive of Phenotypic Aging Status

et al. 2019

View full text Add to dashboard Cite

Background: Recent studies investigating longevity have revealed very few convincing genetic associations with increased lifespan. This is, in part, due to the complexity of biological aging, as well as the limited power of genome-wide association studies, which assay common single nucleotide polymorphisms (SNPs) and require several thousand subjects to achieve statistical significance. To overcome such barriers, we performed comprehensive DNA sequencing of a panel of 20 genes previously associated with phenotypic aging in a cohort of 200 individuals, half of whom were clinically defined by an "early aging" phenotype, and half of whom were clinically defined by a "late aging" phenotype based on age (65-75 years) and the ability to walk up a flight of stairs or walk for 15 min without resting. A validation cohort of 511 late agers was used to verify our results. Results: We found early agers were not enriched for more total variants in these 20 agingrelated genes than late agers. Using machine learning methods, we identified the most predictive model of aging status, both in our discovery and validation cohorts, to be a random forest model incorporating damaging exon variants [Combined Annotation-Dependent Depletion (CADD) > 15]. The most heavily weighted variants in the model were within poly(ADP-ribose) polymerase 1 (PARP1) and excision repair cross complementation group 5 (ERCC5), both of which are involved in a canonical aging pathway, DNA damage repair. Conclusion: Overall, this study implemented a framework to apply machine learning to identify sequencing variants associated with complex phenotypes such as aging. While the small sample size making up our cohort inhibits our ability to make definitive conclusions about the ability of these genes to accurately predict aging, this study offers a unique method for exploring polygenic associations with complex phenotypes.

show abstract

Section: Discussionmentioning

confidence: 99%

Exonic Variants in Aging-Related Genes Are Predictive of Phenotypic Aging Status

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Thus, a deficiency of the vitamins causes a shifting of the balance between these two nucleoside monophosphates towards dUMP resulting in the incorporation of uracil into DNA (Reynolds, 2014). This, together with the impairment of DNA damage repair discovered by our team, that can be, at least partly, attributed to the presence of specific SNP variants, may lead to the introduction of AP sites or DNA strand breaks and apoptosis of neurons, especially in the hippocampus (Young et al 2007;Czarny et al, 2017a). In addition, folate deficiencies are also known to affect mtDNA, causing inter alia an increased number of deletions and thus the induction of oxidative stress (Chou and Huang, 2009;Chou et al, 2007;Kronenberg et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Peer Review #2 of "Single-nucleotide polymorphisms of uracil-processing genes affect the occurrence and the onset of recurrent depressive disorder (v0.1)"

2018

View full text Add to dashboard Cite

Depressive disorders (DD) are known to be associated with increased DNA damage, the impairment of DNA damage repair, and the presence of single-nucleotide polymorphisms (SNPs) in DNA damage repair genes. Some indirect evidence also suggests that uracil metabolism may be disrupted in depressed patients. Therefore, the current study genotypes three SNPs localized in genes encoding uracil-processing proteins: two glycosylases, i.e. UNG g.7245G>C (rs34259), SMUG1 c.-31A>G (rs3087404), and dUTPase, i.e. DUT g.48638795G>T (rs4775748). The polymorphisms were analyzed in 585 DNA samples (282 cases and 303 controls) using TaqMan probes. The G/G genotype and G allele of UNG polymorphism decreased the risk of depression, while the G/C genotype and C allele of the same SNP increased it. It was also found that G/G carriers had their first episode significantly later than the heterozygotes. Although there was no association between the occurrence of depression and the SMUG1 SNP, a significant difference was found between the homozygotes regarding the onset of DD. In conclusion, the SNPs localized in the uracil-processing genes may modulate the occurrence and the onset of depression, which further supports the hypothesis that impairment of DNA damage repair, especially base-excision repair, may play an important role in the pathogenesis of the disease.

show abstract

“…An elevated level of DNA damage was observed in patients with depression. Furthermore, single nucleotide polymorphisms of BER genes may modulate the risk of this disease [ 106 ]. DNA damage and DNA repair also participate in the etiopathology of schizophrenia and autism spectrum disorders [ 45 ].…”

Section: Nucleusmentioning

confidence: 99%

Epigenetics of Subcellular Structure Functioning in the Origin of Risk or Resilience to Comorbidity of Neuropsychiatric and Cardiometabolic Disorders

Campo¹,

Martínez-Rosas²,

Guarner-Lans³

2018

IJMS

View full text Add to dashboard Cite

Mechanisms controlling mitochondrial function, protein folding in the endoplasmic reticulum (ER) and nuclear processes such as telomere length and DNA repair may be subject to epigenetic cues that relate the genomic expression and environmental exposures in early stages of life. They may also be involved in the comorbid appearance of cardiometabolic (CMD) and neuropsychiatric disorders (NPD) during adulthood. Mitochondrial function and protein folding in the endoplasmic reticulum are associated with oxidative stress and elevated intracellular calcium levels and may also underlie the vulnerability for comorbid CMD and NPD. Mitochondria provide key metabolites such as nicotinamide adenine dinucleotide (NAD+), ATP, α-ketoglutarate and acetyl coenzyme A that are required for many transcriptional and epigenetic processes. They are also a source of free radicals. On the other hand, epigenetic markers in nuclear DNA determine mitochondrial biogenesis. The ER is the subcellular organelle in which secretory proteins are folded. Many environmental factors stop the ability of cells to properly fold proteins and modify post-translationally secretory and transmembrane proteins leading to endoplasmic reticulum stress and oxidative stress. ER functioning may be epigenetically determined. Chronic ER stress is emerging as a key contributor to a growing list of human diseases, including CMD and NPD. Telomere loss causes chromosomal fusion, activation of the control of DNA damage-responses, unstable genome and altered stem cell function, which may underlie the comorbidity of CMD and NPD. The length of telomeres is related to oxidative stress and may be epigenetically programmed. Pathways involved in DNA repair may be epigenetically programmed and may contribute to diseases. In this paper, we describe subcellular mechanisms that are determined by epigenetic markers and their possible relation to the development of increased susceptibility to develop CMD and NPD.

show abstract

Impact of Single Nucleotide Polymorphisms of Base Excision Repair Genes on DNA Damage and Efficiency of DNA Repair in Recurrent Depression Disorder

Cited by 35 publications

References 31 publications

Exonic Variants in Aging-Related Genes Are Predictive of Phenotypic Aging Status

Exonic Variants in Aging-Related Genes Are Predictive of Phenotypic Aging Status

Peer Review #2 of "Single-nucleotide polymorphisms of uracil-processing genes affect the occurrence and the onset of recurrent depressive disorder (v0.1)"

Epigenetics of Subcellular Structure Functioning in the Origin of Risk or Resilience to Comorbidity of Neuropsychiatric and Cardiometabolic Disorders

Contact Info

Product

Resources

About