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Title: DNA damage checkpoint recovery and cancer development

Abstract

Cell cycle checkpoints were initially presumed to function as a regulator of cell cycle machinery in response to different genotoxic stresses, and later found to play an important role in the process of tumorigenesis by acting as a guard against DNA over-replication. As a counterpart of checkpoint activation, the checkpoint recovery machinery is working in opposition, aiming to reverse the checkpoint activation and resume the normal cell cycle. The DNA damage response (DDR) and oncogene induced senescence (OIS) are frequently found in precancerous lesions, and believed to constitute a barrier to tumorigenesis, however, the DDR and OIS have been observed to be diminished in advanced cancers of most tissue origins. These findings suggest that when progressing from pre-neoplastic lesions to cancer, DNA damage checkpoint barriers are overridden. How the DDR checkpoint is bypassed in this process remains largely unknown. Activated cytokine and growth factor-signaling pathways were very recently shown to suppress the DDR and to promote uncontrolled cell proliferation in the context of oncovirus infection. In recent decades, data from cell line and tumor models showed that a group of checkpoint recovery proteins function in promoting tumor progression; data from patient samples also showed overexpression of checkpoint recovery proteins inmore » human cancer tissues and a correlation with patients' poor prognosis. In this review, the known cell cycle checkpoint recovery proteins and their roles in DNA damage checkpoint recovery are reviewed, as well as their implications in cancer development. This review also provides insight into the mechanism by which the DDR suppresses oncogene-driven tumorigenesis and tumor progression. - Highlights: • DNA damage checkpoint works as a barrier to cancer initiation. • DDR machinary response to genotoxic and oncogenic stress in similar way. • Checkpoint recovery pathways provide active signaling in cell cycle control. • Checkpoint recovery pathway plays a role in overriding tumor barrier in tumorigenesis. • Recovery protein dysregulation and human cancer development is correlated.« less

Authors:
 [1];  [2];  [1];  [2]
  1. First affiliated hospital, Zhejiang University, School of medicine, Cancer Center, 79 Qingchun Road, Hangzhou 310003 (China)
  2. Department of Genetics, University of Texas M.D. Anderson Cancer Center, Department of Genetics Unit 1010, 1515 Holcombe Blvd. Houston, TX 77030 (United States)
Publication Date:
OSTI Identifier:
22462298
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 334; Journal Issue: 2; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANIMAL TISSUES; BYPASSES; CARCINOGENESIS; CELL CYCLE; CELL PROLIFERATION; DNA; DNA DAMAGES; GROWTH FACTORS; NEOPLASMS; ONCOGENES; PATIENTS; REVIEWS

Citation Formats

Wang, Haiyong, Zhang, Xiaoshan, Teng, Lisong, E-mail: lsteng@zju.edu.cn, and Legerski, Randy J., E-mail: rlegersk@mdanderson.org. DNA damage checkpoint recovery and cancer development. United States: N. p., 2015. Web. doi:10.1016/J.YEXCR.2015.03.011.
Wang, Haiyong, Zhang, Xiaoshan, Teng, Lisong, E-mail: lsteng@zju.edu.cn, & Legerski, Randy J., E-mail: rlegersk@mdanderson.org. DNA damage checkpoint recovery and cancer development. United States. doi:10.1016/J.YEXCR.2015.03.011.
Wang, Haiyong, Zhang, Xiaoshan, Teng, Lisong, E-mail: lsteng@zju.edu.cn, and Legerski, Randy J., E-mail: rlegersk@mdanderson.org. 2015. "DNA damage checkpoint recovery and cancer development". United States. doi:10.1016/J.YEXCR.2015.03.011.
@article{osti_22462298,
title = {DNA damage checkpoint recovery and cancer development},
author = {Wang, Haiyong and Zhang, Xiaoshan and Teng, Lisong, E-mail: lsteng@zju.edu.cn and Legerski, Randy J., E-mail: rlegersk@mdanderson.org},
abstractNote = {Cell cycle checkpoints were initially presumed to function as a regulator of cell cycle machinery in response to different genotoxic stresses, and later found to play an important role in the process of tumorigenesis by acting as a guard against DNA over-replication. As a counterpart of checkpoint activation, the checkpoint recovery machinery is working in opposition, aiming to reverse the checkpoint activation and resume the normal cell cycle. The DNA damage response (DDR) and oncogene induced senescence (OIS) are frequently found in precancerous lesions, and believed to constitute a barrier to tumorigenesis, however, the DDR and OIS have been observed to be diminished in advanced cancers of most tissue origins. These findings suggest that when progressing from pre-neoplastic lesions to cancer, DNA damage checkpoint barriers are overridden. How the DDR checkpoint is bypassed in this process remains largely unknown. Activated cytokine and growth factor-signaling pathways were very recently shown to suppress the DDR and to promote uncontrolled cell proliferation in the context of oncovirus infection. In recent decades, data from cell line and tumor models showed that a group of checkpoint recovery proteins function in promoting tumor progression; data from patient samples also showed overexpression of checkpoint recovery proteins in human cancer tissues and a correlation with patients' poor prognosis. In this review, the known cell cycle checkpoint recovery proteins and their roles in DNA damage checkpoint recovery are reviewed, as well as their implications in cancer development. This review also provides insight into the mechanism by which the DDR suppresses oncogene-driven tumorigenesis and tumor progression. - Highlights: • DNA damage checkpoint works as a barrier to cancer initiation. • DDR machinary response to genotoxic and oncogenic stress in similar way. • Checkpoint recovery pathways provide active signaling in cell cycle control. • Checkpoint recovery pathway plays a role in overriding tumor barrier in tumorigenesis. • Recovery protein dysregulation and human cancer development is correlated.},
doi = {10.1016/J.YEXCR.2015.03.011},
journal = {Experimental Cell Research},
number = 2,
volume = 334,
place = {United States},
year = 2015,
month = 6
}
  • Highlights: •Radiosensitization by PARG silencing was observed in multiple lung cancer cells. •PAR accumulation was enhanced by PARG silencing after DNA damage. •Radiation-induced G2/M arrest and checkpoint activation were impaired by PARG siRNA. -- Abstract: Poly(ADP-ribose) glycohydrolase (PARG) is a major enzyme that plays a role in the degradation of poly(ADP-ribose) (PAR). PARG deficiency reportedly sensitizes cells to the effects of radiation. In lung cancer, however, it has not been fully elucidated. Here, we investigated whether PARG siRNA contributes to an increased radiosensitivity using 8 lung cancer cell lines. Among them, the silencing of PARG induced a radiosensitizing effect inmore » 5 cell lines. Radiation-induced G2/M arrest was largely suppressed by PARG siRNA in PC-14 and A427 cells, which exhibited significantly enhanced radiosensitivity in response to PARG knockdown. On the other hand, a similar effect was not observed in H520 cells, which did not exhibit a radiosensitizing effect. Consistent with a cell cycle analysis, radiation-induced checkpoint signals were not well activated in the PC-14 and A427 cells when treated with PARG siRNA. These results suggest that the increased sensitivity to radiation induced by PARG knockdown occurs through the abrogation of radiation-induced G2/M arrest and checkpoint activation in lung cancer cells. Our findings indicate that PARG could be a potential target for lung cancer treatments when used in combination with radiotherapy.« less
  • The acquisition of genomic instability characterized by aneuploidy and chromosomal rearrangement is an important step in development of human malignancies. To maintain genomic stability, normal eukaryotic cells from yeasts to humans contain a {open_quotes}checkpoint{close_quotes} mechanism. Incomplete DNA replication or DNA damage results in cell cycle arrest in the G1 and G2 phases of the cycle until the damage is repaired. Mutations in the p53 tumor suppressor gene result in loss of the G1 checkpoint and an increase in genomic instability. Although several genes required for the G2 checkpoint in yeast, including RAD9 and MEC1, have been identified, none of themore » human genes are known. Our goal is to isolate additional human checkpoint genes as candidate tumor suppressor genes and study their role in tumorigenesis and radiation sensitivity. We developed a genetic strategy to select for human cDNAs by functional complementation of the yeast checkpoint mutations, rad9 and mec1. Screening of a human cDNA library by this method resulted in the isolation of an active clone, CCC1 (checkpoint complementing cDNA), which complements the damage inducible checkpoint of both the rad9 and mec1 mutant strains. We find greater than fifteen fold increases in resistance to ionizing radiation and damage from a mutant DNA ligase when CCC1 is expressed in either the rad9 or mec1 mutant yeast. From preliminary experiments, CCC1 can also rescue the sensitivity of a rad9 strain to UV damage. In contrast, expression of CCC1 has no effect on the HU sensitivity of a mec1 strain suggesting that it acts to complement the damage inducible checkpoint but not the replication checkpoint. Using a microsatellite repeat in the cDNA, CCC1 was mapped by multipoint linkage to an interval at band 14q32 flanked by D14s68 and GATA13B06. Current experiments are directed towards understanding the role of CCC1 in the mammalian checkpoint mechanism of normal and malignant cells.« less
  • It is proposed that genomic integrity is preserved after DNA damage in a variety of ways. X irradiation induces a p53-dependent G{sub 1}-phase cell cycle checkpoint which putatively allows time for repair of DNA damage. The p53 protein is also involved in the initiation of apoptosis after radiation-induced DNA damage, presumably leading to the elimination of lethally damaged cells from the irradiated population. To test the hypothesis that repair occurs in the additional time provided by the activation of the G{sub 1}-phase checkpoint, we investigated whether the presence of a G{sub 1}-phase arrest modified the frequency and type of chromosomalmore » rearreangements at the first mitosis after irradiation. Isogenic cell lines derived from the same human glioma cell line, but differing in p53 status, were used. Purified G{sub 1}-phase cells, isolated by centrifugal elutriation and X-irradiated, were studied. The wild-type p53 cell line demonstrated a dose-dependent arrest during G{sub 1} phase, as determined by flow cytometry. These cells remained in G{sub 1} phase, as determined by flow cytometry. These cells remained in G{sub 1} phase as long as 48 h after irradiation. Cells expressing a dominant-negative p53 mutation accumulated to a much lesser extent in G{sub 1} phase after irradiation. Cells lacking the G{sub 1}-phase checkpoint showed increased survival at all radiation doses. There were no significant differences in the type or frequency of total chromosomal aberrations in mitotic cells from either cell line after 1,2,4 or 6 Gy X rays, as measured by conventional cytogenetic analysis. There was an increase, however, in the number of reciprocal translocations in mitotic cells with mutant p53 (lacking a G{sub 1}-phase checkpoint), as measured by fluorescence in situ hybridization with a chromosime 4-specifc DNA library, but only after 6 Gy. 47 refs., 6 figs., 2 tabs.« less
  • No abstract prepared.
  • DNA-damage signaling utilizes a multitude of posttranslational modifiers as molecular switches to regulate cell-cycle checkpoints, DNA repair, cellular senescence, and apoptosis. Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We have solved the X-ray crystal structure of the FHA domain structure at 1.35 {angstrom}. We have shown that RNF8 facilitates the accumulation of checkpoint mediator proteins BRCA1 and 53BP1 to the damaged chromatin, on one hand through the phospho-dependent FHA domain-mediated binding of RNF8 to MDC1, on the other hand via its role in ubiquitylating H2AX and possibly other substratesmore » at damage sites. Moreover, RNF8-depleted cells displayed a defective G2/M checkpoint and increased IR sensitivity. Together, our study implicates RNF8 as a novel DNA-damage-responsive protein that integrates protein phosphorylation and ubiquitylation signaling and plays a critical role in the cellular response to genotoxic stress.« less