scholarly journals Identification of inducible damage-recognition proteins that are overexpressed in HeLa cells resistant to cis-diamminedichloroplatinum (II)

1991 ◽  
Vol 277 (3) ◽  
pp. 875-878 ◽  
Author(s):  
C C K Chao ◽  
S L Huang ◽  
L Y Lee ◽  
S Lin-Chao
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Hela Cells ◽  
Cisplatin Resistance ◽  
Damage Recognition ◽  
Modified Dna

Two cis-diamminedichloroplatinum (II) (cisplatin)-inducible proteins [b 130 (approximately 130 kDa) and b95 (approximately 95 kDa]) in HeLa cells that recognize both the cisplatin-modified and u.v.-modified DNA were identified in this study. These damage-recognition proteins were overexpressed in cisplatin-resistant HeLa cells. The results suggest that the damage-recognition proteins are regulated in the cells in response to DNA damage, and they may be important for DNA repair and probably the emergence of cisplatin resistance.

scholarly journals Damage-recognition proteins as a potential indicator of DNA-damage-mediated sensitivity or resistance of human cells to ultraviolet radiation

1992 ◽  
Vol 282 (1) ◽  
pp. 203-207 ◽  
Author(s):  
C C K Chao
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Hela Cells ◽  
Xeroderma Pigmentosum ◽  
Cross Linking ◽  
Damage Recognition ◽  
Modified Dna ◽  
Potential Indicator ◽  
Recognition Protein ◽  
Dna Damage Recognition

We have previously identified damage-recognition proteins that bind to cisplatin[cis-diamminedichloroplatinum(II), a DNA cross-linking agent]- or u.v.-modified DNA in HeLa cells [Chao, Huang, Huang & Lin-Chao (1991) Mol. Cell. Biol. 11, 2075-2080; Chao, Huang, Lee & Lin-Chao (1991) Biochem. J. 277, 875-878]. In the present study we compared damage-recognition proteins in cells expressing different sensitivities to DNA damage. An increase in damage-recognition proteins and an enhancement of plasmid re-activation were detected in HeLa cells resistant to cisplatin and u.v. However, repair-defective cells derived from xeroderma-pigmentosum (a rare skin disease) patients did not express less cisplatin damage-recognition proteins than repair-competent cells, suggesting that damage-recognition-protein expression may not be related to DNA repair. By contrast, cells resistant to DNA damage consistently expressed high levels of u.v.-modified-DNA damage-recognition proteins. The results support the notion that u.v. damage-recognition proteins are different from those that bind to cisplatin. These findings also suggest that the damage-recognition proteins identified could be used as potential indicators of the sensitivity or resistance of cells to u.v.

scholarly journals Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2073
Author(s):  
Beate Köberle ◽  
Sarah Schoch
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Cisplatin Resistance ◽  
Platinum Complexes ◽  
Dna Lesions ◽  
Dna Damage Signaling ◽  
Repair Mechanisms ◽  
P53 Inactivation

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

Maslinic Acid Induces DNA Damage and Impairs DNA Repair in Human Cervical Cancer HeLa Cells

2020 ◽  
Vol 40 (12) ◽  
pp. 6869-6877
Author(s):  
KUNG-WEN LU ◽  
MEI-DUE YANG ◽  
SHU-FEN PENG ◽  
JAW-CHYUN CHEN ◽  
PO-YUAN CHEN ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Hela Cells ◽  
Maslinic Acid ◽  
Human Cervical Cancer

scholarly journals Resolving DNA Damage: Epigenetic Regulation of DNA Repair

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2496 ◽  
Author(s):  
Panagiotis Karakaidos ◽  
Dimitris Karagiannis ◽  
Theodoros Rampias
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Histone Modifications ◽  
Dna Repair Genes ◽  
Chromatin Regulation ◽  
Step Process ◽  
Damage Recognition ◽  
Repair Genes ◽  
Epigenetic Research

Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes, including DNA repair. Chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as DNA and histone modifications, as well as by complexes that remodel nucleosomes. In this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. Moreover, we examine how chromatin is regulated when different pathways of DNA repair are utilized. Furthermore, we review additional modes of regulation of DNA repair, such as through the role of global and localized chromatin states in maintaining expression of DNA repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. Finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and DNA repair in the context cancer treatment.

scholarly journals Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway

2020 ◽  
Author(s):  
Cristian Prieto-Garcia ◽  
Oliver Hartmann ◽  
Michaela Reissland ◽  
Thomas Fischer ◽  
Carina R. Maier ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Tumor Cells ◽  
Dna Damage Response ◽  
Fanconi Anemia ◽  
Cisplatin Resistance ◽  
Chemotherapy Resistance ◽  
Fanconi Anemia Pathway ◽  
Platinum Based Chemotherapy ◽  
Damage Response

AbstractSquamous cell carcinomas (SCC) frequently have a limited response to or develop resistance to platinum-based chemotherapy, and have an exceptionally high tumor mutational burden. As a consequence, overall survival is limited and novel therapeutic strategies are urgently required, especially in light of a rising incidences. SCC tumors express ΔNp63, a potent regulator of the Fanconi Anemia (FA) DNA-damage response pathway during chemotherapy, thereby directly contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 affects the FA DNA repair pathway during cisplatin treatment in SCC, thereby influencing therapy outcome. In an ATR-dependent fashion, USP28 is phosphorylated and activated to positively regulate the DNA damage response. Inhibition of USP28 reduces recombinational repair via an ΔNp63-Fanconi Anemia pathway axis, and weakens the ability of tumor cells to accurately repair DNA. Our study presents a novel mechanism by which tumor cells, and in particular ΔNp63 expressing SCC, can be targeted to overcome chemotherapy resistance.SignificanceLimited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ΔNp63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-ΔNp63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.

scholarly journals Analysis of DNA breaks, DNA damage response, and apoptosis produced by high NaCl

2008 ◽  
Vol 295 (6) ◽  
pp. F1678-F1688 ◽  
Author(s):  
Natalia I. Dmitrieva ◽  
Maurice B. Burg
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Hela Cells ◽  
Cell Types ◽  
Dna Breaks ◽  
Main Subject ◽  
Mrn Complex ◽  
Damage Response

We previously reported that, both in cell culture and in the renal inner medulla in vivo, elevating NaCl increased the number of DNA breaks, which persisted as long as NaCl remained high but were rapidly repaired when NaCl was lowered. Furthermore, those breaks did not induce the DNA repair protein γH2AX or cause activation of the MRN (Mre11, Rad50, Nbs1) complex. In contrast, others recently reported that high NaCl does induce γH2AX and MRN complex formation and concluded that these activities are associated with repair of the DNA (Sheen MR, Kim SW, Jung JY, Ahn JY, Rhee JG, Kwon HM, Woo SK. Am J Physiol Renal Physiol 291: F1014–F1020, 2006). The purpose of the present studies was to resolve the disparity. The important difference is that HeLa cells, which were the main subject of the later report, are much less tolerant of high NaCl than are the mIMCD3 cells, which were our main subject. mIMCD3 cells survive levels of NaCl that kill HeLa cells by apoptosis. Here we demonstrate that in both cell types raising NaCl to a level that the cells survive (higher for mIMCD3 than HeLa) increases DNA breaks without inducing γH2AX or activating the MRN complex and that the DNA breaks persist as long as NaCl remains elevated, but are rapidly repaired when it is lowered. Importantly, in both cell types, raising NaCl further to cause apoptosis activates these DNA damage response proteins and greatly fragments DNA, associated with cell death. We conclude that γH2AX induction and MRN activation in response to high NaCl are associated with apoptosis, not DNA repair.

scholarly journals Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

2020 ◽  
Vol 22 (1) ◽  
pp. 355
Author(s):  
Cho-Yi Chen ◽  
Masaoki Kawasumi ◽  
Tien-Yun Lan ◽  
Chi-Lam Poon ◽  
Yi-Sian Lin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Endoplasmic Reticulum ◽  
Dna Repair ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Progression ◽  
Late Stage ◽  
Cisplatin Resistance ◽  
Nuclear Antigen ◽  
Er Stress Response

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.

How Can Hematopoietic Stem Cells and Myeloid Progenitors Become Transformed?.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1389-1389
Author(s):  
Mary Mohrin ◽  
Emer Bourke ◽  
Ciaran Morrison ◽  
Emmanuelle Passegue
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genotoxic Stress ◽  
Hematopoietic Stem ◽  
Damage Recognition ◽  
Repair Mechanisms ◽  
Apoptotic Genes ◽  
Dna Damage Recognition ◽  
Kinetics Of ◽  
Damaged Dna

Abstract DNA damage can be caused by intrinsic and extrinsic sources, and unrepaired or imprecisely repaired DNA can lead to mutagenesis, cell death, or malignant transformation. Here, we have used highly purified hematopoietic stem cells (HSC) and myeloid progenitor populations (MP: CMP & GMP) to understand how they respond to ionizing radiation (IR) and to establish how they recognize and repair damaged DNA. Our overall goal is to determine whether HSC and MP differ in their ability to deal with genotoxic stress and to identify the type of deregulations that each population requires for accumulating mutations and becoming transformed. By following their ability to form colonies in methylcellulose and to grow in liquid culture, we found that HSC are more capable of withstanding increasing doses of IR than MP. BrdU incorporation pulses revealed that irradiated HSC have an initial and transient pause in proliferation, while irradiated MP cycled faster than untreated MP. By monitoring apoptosis with AnnexinV/7AAD and cleaved caspase 3 staining, we showed that both irradiated HSC and MP have an immediate apoptotic response but that HSC quickly recover and restore low baseline levels of apoptosis while MP maintain high levels of apoptosis. These results suggest that HSC may pause cycling to repair damaged DNA while MP increase cycling to replenish cells cleared by apoptosis. At the molecular level, irradiated HSC displayed a strong and transient induction of several pro-apoptotic genes (bax, puma, noxa) but minimal change in expression of pro-survival genes, which are already high in those cells. In contrast, irradiated MP displayed minimal induction of pro-apoptotic genes (except for puma) but decreased expression of pro-survival genes, which are already low in those cells. Taken together, these results suggest that HSC can withstand genotoxic stress better than MP due to differences in the regulation of their apoptotic machinery leading to protection of HSC and elimination of MP. To monitor the ability of HSC and MP to recognize and repair damaged DNA, we used immunofluorescence techniques to study IR-induced DNA damage foci. Irradiated HSC and MP displayed similar kinetics of DNA damage recognition as monitored by the formation and resolution of gamma-H2AX and 53BP1 foci. In contrast, the kinetics of Rad51 foci – which signal the initiation of homologous recombination (HR) DNA repair – significantly differed between these populations. While Rad51 foci were immediately induced and quickly resolved in MP, very few Rad51 foci were formed in HSC up to 12 hours post-IR. Since HR only occurs during S/G2/M phases of the cell cycle, it is possible that the largely quiescent HSC can not utilize HR and instead use the more error prone DNA repair mechanism non-homologous end joining (NHEJ). At the molecular level, both HSC and MP displayed similar levels of genes associated with DNA damage recognition and repair (atm, rad50) and specific to HR (brca1), while MP display significantly lower levels of genes specifically involved in NHEJ (ku80) compared to HSC. These results indicate that both HSC and MP can recognize damaged DNA but might preferentially use different repair mechanisms. They also suggest that to become transformed and drive leukemia development, HSC might only require DNA damage, while MP might also need deregulation affecting both DNA repair mechanisms and apoptosis machinery. These findings provide insights into the mechanisms that maintain homeostatic function of hematopoietic stem and progenitor cells in normal tissues, and the deregulations that can occur during aging and cancer development. Ultimately, they could identify molecular targets to prevent therapy-related organ damage or secondary leukemia.

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