Adimoolam S, Ford JMP53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair (Amst) 2:947-954

Department of Medicine (Oncology), Stanford University School of Medicine, 1115 CCSR Building, 269 Campus Drive, Stanford, CA 94305, USA.
DNA Repair (Impact Factor: 3.11). 10/2003; 2(9):947-54. DOI: 10.1016/S1568-7864(03)00087-9
Source: PubMed


In response to a variety of types of DNA damage, the p53 tumor suppressor gene product is activated and regulates a number of downstream cellular processes such as cell cycle arrest, apoptosis and DNA repair. Recent discoveries concerning the regulation of DNA repair processes by p53, such as nucleotide excision repair (NER) and base excision repair (BER) have paved the way for studies to understand the mechanisms governing p53-dependent DNA repair. Although several theories have been proposed, accumulating evidence points to a transcriptional regulatory role for p53 in NER, mediating expression of the global genomic repair (GGR)-specific damage recognition genes, DDB2 and XPC. In BER, a more direct role for p53 has been proposed, potentially acting through protein-protein interactions with BER specific factors. These advances have greatly enhanced our understanding of the role of p53 in DNA repair and this review comprehensively summarizes current opinions on the mechanisms of p53-dependent DNA repair.

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Available from: James Ford, Dec 30, 2013
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    • "The gene contains 11 exons, which encode 2.8 kb mRNA that is translated into a 53 kDa protein. Following exposure to stress conditions, including hypoxia, oncogene activation, DNA damage, nucleotide defects and viral transformation, p53 is subjected to certain post-translational modifications that regulate the subcellular localization and stability of the protein (2–5). Under these stress conditions, there are three cellular outcomes: i) Repair mechanisms are prompted (5); ii) if there is no way to avoid it, the cells undergo apoptosis or cell cycle arrest (6–17); and iii) the cells defense mechanisms are affected and the cells become cancerous. "
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    ABSTRACT: Radiotherapy serves as adjunctive treatment to chemotherapy and surgical resection of colorectal cancer. However, the cellular response to irradiation varies depending on the expression of tumor suppressor p53, which plays a significant role in the regulation of cell cycle arrest, apoptosis and telomerase activity in various cancers. The present study aimed to investigate cell cycle arrest, apoptosis and telomerase activity with respect to p53 expression in p53 wild-type (+/+) and deficient (-/-) HCT116 colon cancer cell lines following 5 Gy γ-irradiation. Cell cycle arrest and apoptosis were evaluated using flow cytometry. The telomerase activity was measured using a TRAP (telomerase repeat amplification protocol) assay. Following treatment with irradiation, G1/S cell cycle arrest occurred in the p53+/+ cells, whereas the p53-/- cells accumulated in the G2 phase. No differences were observed in the apoptotic ratios between the two cell lines following irradiation. Decreased telomerase activity was observed in the p53+/+ cells, whereas telomerase activity was increased in the p53-/- cells. The results showed that while telomerase activity and G1 cell cycle arrest were regulated depending on the p53 status, G2 arrest and the apoptotic response were promoted via a p53-independent pathway.
    Oncology letters 09/2013; 6(3):807-810. DOI:10.3892/ol.2013.1441 · 1.55 Impact Factor
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    • "However, the persistence of nicked DNA throughout stages IX to XII seminiferous tubules, as well as significant increase of nicked chromatin in the pool of mature caput sperm of FD-treated rats, indicated the failure of a FSH-mediated chromatin repair mechanism, operative in the elongating spermatids of stages XI to XII tubules [63,67]. It is therefore averred that FSH-mediated histone acetylations, occurring at specific sites during the relaxation of DNA, may be involved in the recruitment of crucial DNA repair proteins, namely transition protein1, p53, DNA polymerase [24,50,69,70]. We had reported in the past the loss of at least one repair protein, namely transition protein1 in the testis of FD-treated rats [44]. "
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    ABSTRACT: Background The putative regulatory role of the male reproductive hormones in the molecular mechanism underlying chromatin condensation remains poorly understood. In the past decade, we developed two adult male rat models wherein functional deficits of testosterone or FSH, produced after treatments with 20 mg/Kg/d of cyproterone acetate (CPA) per os, for a period of 15 days or 3 mg/Kg/d of fluphenazine decanoate (FD) subcutaneously, for a period of 60 days, respectively, affected the rate of sperm chromatin decondensation in vitro. These rat models have been used in the current study in order to delineate the putative roles of testosterone and FSH in the molecular mechanism underlying remodelling of sperm chromatin. Results We report that deficits of both testosterone and FSH affected the turnover of polyubiquitylated histones and led to their accumulation in the testis. Functional deficits of testosterone reduced expression of MIWI, the 5-methyl cap binding RNA-binding protein (PIWIlike murine homologue of the Drosophila protein PIWI/P-element induced wimpy testis) containing a PAZ/Piwi-Argonaut-Zwille domain and levels of histone deacetylase1 (HDAC1), ubiquitin ligating enzyme (URE-B1/E3), 20S proteasome α1 concomitant with reduced expression of ubiquitin activating enzyme (ube1), conjugating enzyme (ube2d2), chromodomain Y like protein (cdyl), bromodomain testis specific protein (brdt), hdac6 (histone deacetylase6), androgen-dependent homeobox placentae embryonic protein (pem/RhoX5), histones h2b and th3 (testis-specific h3). Functional deficits of FSH reduced the expression of cdyl and brdt genes in the testis, affected turnover of ubiquitylated histones, stalled the physiological DNA repair mechanism and culminated in spermiation of DNA damaged sperm. Conclusions We aver that deficits of both testosterone and FSH differentially affected the process of sperm chromatin remodelling through subtle changes in the ‘chromatin condensation transcriptome and proteome’, thereby stalling the replacement of ‘dynamic’ histones with ‘inert’ protamines, and altering the epigenetic state of condensed sperm chromatin. The inappropriately condensed chromatin affected the sperm chromatin cytoarchitecture, evident from subtle ultrastructural changes in the nuclei of immature caput epididymal sperm of CPA- or FD-treated rats, incubated in vitro with dithiothreitol.
    12/2012; 4(1):23. DOI:10.1186/1868-7083-4-23
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    • "Initially, p53 protein levels are increased via the inhibition of its interaction with negative regulators such as the murine double minute 2 protein (MDM2). Then, induced p53 functions through protein–protein interactions and/or as a transcription factor increasing the expression of downstream genes, such as p21 (cyclindependent kinase inhibitor), GADD45a (growth arrest and DNA damage induced 45, alpha) and bax (bcl2-associated X protein), all involved in cell cycle regulation pathways, namely cell cycle arrest, DNA repair and/or apoptosis (Adimoolam and Ford 2003) (Fig. 1). Since previous research has shown that EE 2 alters hepatic mRNA abundance of key NER genes in adult zebrafish (Notch et al. 2007; Notch and Mayer 2009a, b), we hypothesize that the alteration of DNA repair processes by EE 2 in gonads may be associated with the embryonic disruption of zebrafish development as observed in a previous study (Soares et al. 2009). "
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    ABSTRACT: Parental full life-cycle exposure to ethinylestradiol (EE₂) significantly affects embryo development and survival. One of the possible mechanisms of action of EE₂ may involve the impairment of an organism's ability to repair DNA damage. DNA repair mechanisms have sophistically evolved to overcome DNA damaging hazards that threaten the integrity of the genome. In the present study, changes in the transcription levels of key genes involved in two of the most thoroughly studied DNA repair systems in mammals were evaluated in adult zebrafish (Danio rerio) gonad upon full life-cycle exposure to chronic environmentally low levels of EE₂ (i.e., 0.5, 1 and 2 ng/L EE₂). Real time PCR was used to analyse the expression levels of nucleotide excision repair genes (NER) as well as the tumor suppressor p53 and downstream selected effectors, i.e., p21 (cyclin-dependent kinase inhibitor), GADD45α (growth arrest and DNA damage induced 45, alpha), bax (bcl2-associated X protein) and p53 key regulator MDM2 (murine double minute 2 protein). NER genes transcription levels in gonads did not differ significantly among treatments. In contrast, the number of transcripts of p53 gene was significantly increased in male gonads at all EE₂ exposure concentrations and in females at 1 ng/L EE₂. Despite the increase in p53 transcripts, transcription levels of p21, GADD45α and bax genes were not affected upon EE₂ treatment, whereas MDM2 gene expression significantly increased in females at the intermediate EE₂ dose (1 ng/L). Overall, the present study indicate that chronic low levels of EE₂ significantly modulates the transcription of p53, a key gene involved in DNA repair, particularly in male zebrafish gonads, which supports the hypothesis of an impact of EE2 in male gonad DNA repair pathways.
    Ecotoxicology 04/2012; 21(5):1513-22. DOI:10.1007/s10646-012-0905-4 · 2.71 Impact Factor
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