CUX2 Protein Functions as an Accessory Factor in the Repair of Oxidative DNA Damage

Pal, Ranjana; Ramdzan, Zubaidah M.; Kaur, Simran; Duquette, Philippe M.; Marcotte, Richard; Leduy, Lam; Davoudi, Sayeh; Lamarche-Vane, Nathalie; Iulianella, Angelo; Nepveu, Alain

doi:10.1074/jbc.m115.651042

Cited by 46 publications

(43 citation statements)

References 88 publications

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“…In a previous study of the CUX2 protein, we showed that the ability of a CUT domain to stimulate OGG1 was reduced following the introduction of two point mutations replacing glutamic acids to alanines [54]. In the present study, we have engineered the same point mutations with the CUT domain 1 of CUX1 (Figure 6A: C1-2Ala).…”

Section: Resultsmentioning

confidence: 83%

The DNA repair function ofCUX1contributes to radioresistance

et al. 2017

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Ionizing radiation generates a broad spectrum of oxidative DNA lesions, including oxidized base products, abasic sites, single-strand breaks and double-strand breaks. The CUX1 protein was recently shown to function as an auxiliary factor that stimulates enzymatic activities of OGG1 through its CUT domains. In the present study, we investigated the requirement for CUX1 and OGG1 in the resistance to radiation. Cancer cell survival following ionizing radiation is reduced by CUX1 knockdown and increased by higher CUX1 expression. However, CUX1 knockdown is sufficient by itself to reduce viability in many cancer cell lines that exhibit high levels of reactive oxygen species (ROS). Consequently, clonogenic results expressed relative to that of non-irradiated cells indicate that CUX1 knockdown confers no or modest radiosensitivity to cancer cells with high ROS. A recombinant protein containing only two CUT domains is sufficient for rapid recruitment to DNA damage, acceleration of DNA repair and increased survival following radiation. In agreement with these findings, OGG1 knockdown and treatment of cells with OGG1 inhibitors sensitize cancer cells to radiation. Together, these results validate CUX1 and more specifically the CUT domains as therapeutic targets.

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Section: Resultsmentioning

confidence: 83%

The DNA repair function ofCUX1contributes to radioresistance

et al. 2017

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“…Moreover, the risk C allele of rs6490061 was associated with a higher CUX2 mRNA expression ( P = 0.0153, Figure C). Because CUX2 functions as an accessory factor that promotes the repair of oxidative DNA damage, H. pylori infection might suppress CUX2 expression and subsequently increase gastric cancer risk by damaging the DNA repair pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Because CUX2 functions as an accessory factor that promotes the repair of oxidative DNA damage, 42 H. pylori infection might suppress CUX2 expression and subsequently increase gastric cancer risk by damaging the DNA repair pathway. The cluster of DEFB family genes is located on 20q11.21 ( Figure 2).…”

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confidence: 99%

Genome‐wide association study identifies gastric cancer susceptibility loci at 12q24.11‐12 and 20q11.21

Tanikawa

Kamatani

Toyoshima³

et al. 2018

Cancer Science

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Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large‐scale genome‐wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11‐12 (rs6490061, P = 3.20 × 10−8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10−10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10−13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10−11), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.

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“…CAND2 gene encodes a TATA-binding protein, TIP120b, which is muscle-specific and critical for myogenesis, and the eQTL analyses also indicate that the risk allele is associated with increased expression of CAND2 [21]. Expression of CUX2 in post-mitotic neurons contributes to the maintenance of genome integrity through its stimulation of oxidative DNA damage repair [25]. Interesting, CUX2 loci were also significantly associated with ischemic stroke [21].…”

Section: Discussionmentioning

confidence: 99%

NEURL rs6584555 and CAND2 rs4642101 contribute to postoperative atrial fibrillation: a prospective study among Chinese population

Wei

Shen

et al. 2016

Oncotarget

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Postoperative atrial fibrillation (POAF) is a serious, common complication after coronary artery bypass grafting (CABG) surgery. Recently, 5 novel loci were identified to be associated with atrial fibrillation susceptibility using a combination of genotyping, eQTL mapping, and functional validation. In current study, we aim to evaluated the positive findings for POAF susceptibility after CABG among Chinese population, using a population-based, two-stage, nested case-control study with 1,400 patients. NEURL rs12415501 and CAND2 rs4642101 were significantly associated with POAF susceptibility after CABG among Chinese population in both stages. When pooled together, the ORs for each additional copy of minor allele was 1.29 (95% CI: 1.13-1.48, P = 1.7×10−4) for NEURL rs12415501, and 1.21 (95% CI: 1.08-1.36, P = 9.8×10−4) for CAND2 rs4642101. Functional validation experiments found the AF risk allele of NEURL rs6584555 and CAND2 rs4642101 correlated with an increased expression of its corresponding genes (P<0.001). In this independently collected cardiac surgery cohort, we replicated the previous findings, and 2 novel loci are independently associated with POAF risk in patients who undergo CABG surgery in Chinese population.

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CUX2 Protein Functions as an Accessory Factor in the Repair of Oxidative DNA Damage

Cited by 46 publications

References 88 publications

The DNA repair function ofCUX1contributes to radioresistance

The DNA repair function ofCUX1contributes to radioresistance

Genome‐wide association study identifies gastric cancer susceptibility loci at 12q24.11‐12 and 20q11.21

NEURL rs6584555 and CAND2 rs4642101 contribute to postoperative atrial fibrillation: a prospective study among Chinese population

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