R152C DNA Pol β mutation impairs base excision repair and induces cellular transformation

Zhou, Ting; Pan, Feiyan; Cao, Yan; Han, Ying; Zhao, Jing; Sun, Hanyong; Zhou, Xiao‐Long; Wu, Xuping; He, Lingfeng; Hu, Zhigang; Chen, Haoyan; Shen, Binghui; Guo, Zhigang

doi:10.18632/oncotarget.6849

Cited by 21 publications

(23 citation statements)

References 53 publications

(52 reference statements)

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“…Numerous reports indicate that dysregulated lncRNA expression may be implicated in various aspects of tumor, including carcinogenesis, progression, and metastasis 30 - 32 . Some lncRNAs are considered to be useful biomarkers to predict prognosis in GC patients, such as HULC and LINC00668 11 , 33 .…”

Section: Discussionmentioning

confidence: 99%

Differentially Expressed lncRNAs in Gastric Cancer Patients: A Potential Biomarker for Gastric Cancer Prognosis

Tian¹,

Zhu²,

Yan³

et al. 2017

J. Cancer

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Current studies indicate that long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers and implicated with prognosis in gastric cancer (GC). We intended to generate a multi-lncRNA signature to improve prognostic prediction of GC. By analyzing ten paired GC and adjacent normal mucosa tissues, 339 differentially expressed lncRNAs were identified as the candidate prognostic biomarkers in GC. Then we used LASSO Cox regression method to build a 12-lncRNA signature and validated it in another independent GEO dataset. An innovative 12-lncRNA signature was established, and it was significantly associated with the disease free survival (DFS) in the training dataset. By applying the 12-lncRNA signature, the training cohort patients could be categorized into high-risk or low-risk subgroup with significantly different DFS (HR = 4.52, 95%CI= 2.49-8.20, P < 0.0001). Similar results were obtained in another independent GEO dataset (HR=1.58, 95%CI=1.05 - 2.38, P=0.0270). Further analysis showed that the prognostic value of this 12-lncRNA signature was independent of AJCC stage and postoperative chemotherapy. Receiver operating characteristic (ROC) analysis showed that the area under receiver operating characteristic curve (AUC) of combined model reached 0.869. Additionally, a well-performed nomogram was constructed for clinicians. Moreover, single-sample gene-set enrichment analysis (ssGSEA) showed that a group of pathways related to drug resistance and cancer metastasis significantly enriched in the high risk patients. A useful innovative 12-lncRNA signature was established for prognostic evaluation of GC. It might complement clinicopathological features and facilitate personalized management of GC.

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Section: Discussionmentioning

confidence: 99%

Differentially Expressed lncRNAs in Gastric Cancer Patients: A Potential Biomarker for Gastric Cancer Prognosis

Tian¹,

Zhu²,

Yan³

et al. 2017

J. Cancer

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“…The BER assay was performed as described previously (Guo et al, 2009, Zhou et al, 2016). Reactions were carried out in 20 μl of reaction buffer B (40 mM HEPES-KOH [pH 7.8], 70 mM KCI, 7 mM MgCl 2 , 1 mM dithiothreitol, 0.5 mM EDTA, 2 mM ATP, 50 μM each of dATP, dTTP, and dGTP, and 2 μCi [α-32P]-dCTP).…”

Section: Methodsmentioning

confidence: 99%

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

Zhang

Sun

et al. 2016

EBioMedicine

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DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells. We showed that manipulating FEN1 levels in cells alters the response of cancer cells to chemotherapeutic drugs. Furthermore, we identified a small molecular compound, SC13 that specifically inhibits FEN1 activity, thereby interfering with DNA replication and repair in vitro and in cells. SC13 suppresses cancer cell proliferation and induces chromosome instability and cytotoxicity in cells. Importantly, SC13 sensitizes cancer cells to DNA damage-inducing therapeutic modalities and impedes cancer progression in a mouse model. These findings could establish a paradigm for the treatment of breast cancer and other cancers as well.

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“…Many tumors examined to date may express Pol β variant proteins that are predicted to have a single amino acid substitution. It has been reported that some of these variants, such as E295K 43,44 , Y265C 45 , and R152C 46 , are associated with reduced DNA polymerase activity, potentially leading to genome instability and/or cellular transformation. Besides these examples, deletions of exon II or exon XI and a mRNA with a 107-nucleotide insertion between exon IX and exon X have been suggested to be linked to the development of colon cancer and Werner’s syndrome, respectively, by others 25,26 .…”

Section: Discussionmentioning

confidence: 99%

The Pol β variant containing exon α is deficient in DNA polymerase but has full dRP lyase activity

Dai

Prasad

Wilson

2019

Sci Rep

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DNA polymerase (Pol) β is a key enzyme in base excision repair (BER), an important repair system for maintaining genomic integrity. We previously reported the presence of a Pol β transcript containing exon α (105-nucleotide) in normal and colon cancer cell lines. The transcript carried an insertion between exons VI and VII and was predicted to encode a ~42 kDa variant of the wild-type 39 kDa enzyme. However, little is known about the biochemical properties of the exon α-containing Pol β (exon α Pol β) variant. Here, we first obtained evidence indicating expression of the 42 kDa exon α Pol β variant in mouse embryonic fibroblasts. The exon α Pol β variant was then overexpressed in E. coli , purified, and characterized for its biochemical properties. Kinetic studies of exon α Pol β revealed that it is deficient in DNA binding to gapped DNA, has strongly reduced polymerase activity and higher K m for dNTP during gap-filling. On the other hand, the 5′-dRP lyase activity of the exon α Pol β variant is similar to that of wild-type Pol β. These results indicate the exon α Pol β variant is base excision repair deficient, but does conduct 5′-trimming of a dRP group at the gap margin. Understanding the biological implications of this Pol β variant warrants further investigation.

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R152C DNA Pol β mutation impairs base excision repair and induces cellular transformation

Cited by 21 publications

References 53 publications

Differentially Expressed lncRNAs in Gastric Cancer Patients: A Potential Biomarker for Gastric Cancer Prognosis

Differentially Expressed lncRNAs in Gastric Cancer Patients: A Potential Biomarker for Gastric Cancer Prognosis

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

The Pol β variant containing exon α is deficient in DNA polymerase but has full dRP lyase activity

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