dna repair
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2022 ◽  
Vol 163 ◽  
pp. 44-54
Marika Sculco ◽  
Marta La Vecchia ◽  
Anna Aspesi ◽  
Giulia Pinton ◽  
Michela G. Clavenna ◽  

2022 ◽  
Vol 22 (1) ◽  
pp. 100603
Zhixian Zhou ◽  
Huan Yin ◽  
Suye Suye ◽  
Fang Zhu ◽  
Haiyi Cai ◽  

2022 ◽  
Vol 11 ◽  
Zhihong Gong ◽  
Mary E. Platek ◽  
Cathee Till ◽  
Phyllis J. Goodman ◽  
Catherine M. Tangen ◽  

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

2022 ◽  
Daniel Gomez-Cabello ◽  
Georgios Pappas ◽  
Diana Aguilar-Morante ◽  
Christoffel Dinant ◽  
Jiri Bartek

The RNA world is changing our views about sensing and resolution of DNA damage. Here, we developed single-molecule DNA/RNA analysis approaches to visualize how nascent RNA facilitates the repair of DNA double-strand breaks (DSBs). RNA polymerase II (RNAPII) is crucial for DSB resolution in human cells. DSB-flanking, RNAPII-generated nascent RNA forms RNA:DNA hybrids, guiding the upstream DNA repair steps towards favouring the error-free Homologous Recombination (HR) pathway over Non-Homologous End Joining. Specific RNAPII inhibitor, THZ1, impairs recruitment of essential HR proteins to DSBs, implicating nascent RNA in DNA end resection, initiation and execution of HR repair. We further propose that resection factor CtIP interacts with and re-activates RNAPII when paused by the RNA:DNA hybrids, collectively promoting faithful repair of chromosome breaks to maintain genomic integrity.

Iain A. Richard ◽  
Joshua T. Burgess ◽  
Kenneth J. O’Byrne ◽  
Emma Bolderson

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

2022 ◽  
Lyubov N. Chuvakova ◽  
Sergey Yu. Funikov ◽  
Artem I. Davletshin ◽  
Irina B. Fedotova ◽  
Mikhail B. Evgen'ev ◽  

Audiogenic epilepsy (AE), developing in rodent strains in response to sound, is widely used as the model of generalized convulsive epilepsy, while the molecular mechanisms determining AE are currently poorly understood. The brain region that is crucial for AE development isthe inferior and superior colliculi (IC, SC). We compared IC-SC gene expression profiles in rats with different AE susceptibility using transcriptome analysis.The transcriptomes were obtained from the IC-SC of Wistar rats (with no AE), Krushinsky-Molodkina (KM) strain rats (100% AE susceptible), and ”0” strain rats (with no AE) selected from F2 KM x Wistar hybrids for AE absence. KM gene expression displayed characteristic differences inboth of the strains that were not susceptible to AE. There was increased expression of a number of genes responsible for positive regulation of the MAPK signaling cascade, as well as of genes responsible for the production of interferon and several other cytokines. An increase in the expression levels of theTTR gene was found in KM rats, as well as significantly lower expression of the Msh3 gene (involved in post-replicative DNA repair systems). AE was also describedin the 101/HY mouse strain with a mutation in the locus controlling DNA repair. The DNA repair system defects could be the primary factor leading to the accumulation of mutations, which, in turn, promote AE. Keywords: udiogenic seizure, KM strain, transcriptome, TTR gene, Msh3 gene, DNA repair

Kaori Hayashi

AbstractRecent studies have demonstrated the association of altered epigenomes with lifestyle-related diseases. Epigenetic regulation promotes biological plasticity in response to environmental changes, and such plasticity may cause a ‘memory effect’, a sustained effect of transient treatment or an insult in the course of lifestyle-related diseases. We investigated the significance of epigenetic changes in several genes required for renal integrity, including the nephrin gene in podocytes, and the sustained anti-proteinuric effect, focusing on the transcription factor Krüppel-like factor 4 (KLF4). We further reported the role of the DNA repair factor lysine-acetyl transferase 5 (KAT5), which acts coordinately with KLF4, in podocyte injury caused by a hyperglycemic state through the acceleration of DNA damage and epigenetic alteration. In contrast, KAT5 in proximal tubular cells prevents acute kidney injury via glomerular filtration regulation by an epigenetic mechanism as well as promotion of DNA repair, indicating the cell type-specific action and roles of DNA repair factors. This review summarizes epigenetic alterations in kidney diseases, especially DNA methylation, and their utility as markers and potential therapeutic targets. Focusing on transcription factors or DNA damage repair factors associated with epigenetic changes may be meaningful due to their cell-specific expression or action. We believe that a better understanding of epigenetic alterations in the kidney will lead to the development of a novel strategy for chronic kidney disease (CKD) treatment.

2022 ◽  
Vol 13 (1) ◽  
Markus Schick ◽  
Le Zhang ◽  
Sabine Maurer ◽  
Hans Carlo Maurer ◽  
Konstandina Isaakaidis ◽  

AbstractSUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 353
Jordi Minguillón ◽  
María José Ramírez ◽  
Llorenç Rovirosa ◽  
Pilar Bustamante-Madrid ◽  
Cristina Camps-Fajol ◽  

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

2022 ◽  
Vol 12 ◽  
Lihua Wang ◽  
Yanlong Liu ◽  
Li Gao ◽  
Xiaocui Yang ◽  
Xu Zhang ◽  

Genetic dissection of forage yield traits is critical to the development of sorghum as a forage crop. In the present study, association mapping was performed with 85,585 SNP markers on four forage yield traits, namely plant height (PH), tiller number (TN), stem diameter (SD), and fresh weight per plant (FW) among 245 sorghum accessions evaluated in four environments. A total of 338 SNPs or quantitative trait nucleotides (QTNs) were associated with the four traits, and 21 of these QTNs were detected in at least two environments, including four QTNs for PH, ten for TN, six for SD, and one for FW. To identify candidate genes, dynamic transcriptome expression profiling was performed at four stages of sorghum development. One hundred and six differentially expressed genes (DEGs) that were enriched in hormone signal transduction pathways were found in all stages. Weighted gene correlation network analysis for PH and SD indicated that eight modules were significantly correlated with PH and that three modules were significantly correlated with SD. The blue module had the highest positive correlation with PH and SD, and the turquoise module had the highest negative correlation with PH and SD. Eight candidate genes were identified through the integration of genome-wide association studies (GWAS) and RNA sequencing. Sobic.004G143900, an indole-3-glycerol phosphate synthase gene that is involved in indoleacetic acid biosynthesis, was down-regulated as sorghum plants grew in height and was identified in the blue module, and Sobic.003G375100, an SD candidate gene, encoded a DNA repair RAD52-like protein 1 that plays a critical role in DNA repair-linked cell cycle progression. These findings demonstrate that the integrative analysis of omics data is a promising approach to identify candidate genes for complex traits.

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