Dual RNA 3’-end processing of H2A.X messenger RNA maintains DNA damage repair throughout the cell cycle

AbstractPhosphorylated H2A.X is a critical chromatin marker of DNA damage repair (DDR) in higher eukaryotes. However, H2A.X gene expression remains relatively uncharacterised. Replication-dependent (RD) histone genes generate poly(A)- mRNA encoding new histones to package DNA during replication. In contrast, replication-independent (RI) histone genes synthesise poly(A)+ mRNA throughout the cell cycle, translated into histone variants that confer specific epigenetic patterns on chromatin. Remarkably H2AFX, encoding H2A.X, is a hybrid histone gene, generating both poly(A)+ and poly(A)- mRNA isoforms. Here we report that the selective removal of either mRNA isoform reveals different effects in different cell types. In some cells, RD H2A.X poly(A)- mRNA generates sufficient histone for deposition onto DDR associated chromatin. In contrast, cells making predominantly poly(A)+ mRNA require this isoform for de novo H2A.X synthesis, required for efficient DDR. This highlights the importance of differential H2A.X mRNA 3’-end processing in the maintenance of effective DDR.

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PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

Cell Death and Disease ◽

10.1038/s41419-020-2708-5 ◽

2020 ◽

Vol 11 (7) ◽

Author(s):

Nan Huang ◽

Chang Xu ◽

Liang Deng ◽

Xue Li ◽

Zhixuan Bian ◽

...

Keyword(s):

Dna Damage ◽

Histone Deacetylase ◽

Dna Damage Response ◽

De Novo ◽

Dna Damage Repair ◽

Histone Deacetylase 1 ◽

Damage Repair ◽

Damage Response

AbstractPhosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.

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Human POLD1 modulates cell cycle progression and DNA damage repair

BMC Biochemistry ◽

10.1186/s12858-015-0044-7 ◽

2015 ◽

Vol 16 (1) ◽

Cited By ~ 16

Author(s):

Jing Song ◽

Ping Hong ◽

Chengeng Liu ◽

Yueqi Zhang ◽

Jinling Wang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Dna Damage Repair ◽

Cycle Progression ◽

Damage Repair

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Effects of different doses of X‑ray irradiation on cell apoptosis, cell cycle, DNA damage repair and glycolysis in HeLa cells

Oncology Letters ◽

10.3892/ol.2018.9566 ◽

2018 ◽

Cited By ~ 3

Author(s):

Hong Zhao ◽

Yafei Zhuang ◽

Ruibin Li ◽

Yinyin Liu ◽

Zijie Mei ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Hela Cells ◽

Cell Apoptosis ◽

Dna Damage Repair ◽

X Ray ◽

Damage Repair ◽

Different Doses

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Cell Cycle Checkpoints and DNA Damage Repair

Cellular Signaling in Health and Disease - Biological and Medical Physics, Biomedical Engineering ◽

10.1007/978-0-387-98173-4_10 ◽

2009 ◽

pp. 201-225

Author(s):

Martin Beckerman

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cell Cycle Checkpoints ◽

Damage Repair

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Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15555794826018 ◽

2020 ◽

Vol 28 (1) ◽

pp. 33-40 ◽

Cited By ~ 3

Author(s):

Annemarie E. M. Post ◽

Johan Bussink ◽

Fred C. G. J. Sweep ◽

Paul N. Span

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cross Resistance ◽

Damage Repair ◽

Breast Cancer Cohort ◽

Tamoxifen Resistant ◽

Repair Genes

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

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