Science Inventory

DNA DAMAGE REPAIR AND CELL CYCLE CONTROL: A NATURAL BIO-DEFENSE MECHANISM

Citation:

Mudipalli, A. DNA DAMAGE REPAIR AND CELL CYCLE CONTROL: A NATURAL BIO-DEFENSE MECHANISM. Presented at Molecular Maneuverings in Biological Defense Systems National Symposium organized by: Sri Sathya Sai Institute of Higer Learning, Prasanthi Nilayam, India, August 8-10, 2003.

Description:

DNA DAMAGE REPAIR AND CELL CYCLE CONTROL: A natural bio-defense mechanism
Anuradha Mudipalli.

Maintenance of genetic information, including the correct sequence of nucleotides in DNA, is essential for replication, gene expression, and protein synthesis. DNA lesions onto oncogenes or tumor suppressor genes may lead to cell cycle arrest, programmed cell death, mutagenesis, genomic instability and cancer. In addition to endogenous replication errors, DNA is also damaged by environmental mutagens such as UV light, polycyclic aromatic hydrocarbons (PAHs), and agents that induce reactive oxygen species (ROS) generated by oxygen metabolism. Diverse DNA repair systems have evolved to remove DNA lesions from endogenous and exogenous sources. DNA replication errors are corrected by mismatch repair systems, where mis-paired DNA bases are recognized and removed from the newly synthesized DNA strand shortly after DNA replication. Other spontaneous DNA alterations include deamination, hydrolysis, nonenzymatic methylation of DNA bases, and DNA damage induced by ROS. The spontaneous or chemicalinduced DNA lesions include, DNA single- and double- strand breaks, apurinic/apyrimidinic (AP) sites, DNA protein cross-links and DNA base modifications. Among these base modifications, 7,8-dihydro-8oxoguanine (8oxoguanine) is mutagenic by G-T transversions and thus may play an important role in carcinogenesis. Oxidative DNA lesions including strand breaks and AP sites as well as other types of DNA base alterations are eliminated by base excision repair (BER). DNA damage induced by environmental mutagens is also repaired by nucleotide excision repair (NER). NER is the most versatile repair system involved in the removal of structurally unrelated bulky adducts that cause significant helical distortions, including DNA damage induced by UV radiation and also more stable adducts formed by compounds like Benzo[a]pyrene. Lastly, DNA double strand breaks as well as DNA-DNA interstrand cross links induced, for example, by cytoplasmic platinum-based drugs are repaired by homologous or illegitimate recombination processes.

DNA damage, in addition to alerting the DNA repair processes, also regulates cell cycle progression by DNA damage checkpoints, which are highly interactive networks. These checkpoints, in general, control the cell's ability to arrest the cell cycle in response to DNA damage, regulate the activation of DNA repair pathways, the activation of a transcriptional program, and even programmed cell death (apoptosis) in the case of heavy damage. All these control mechanisms operate throughout the cell cycle and there are three important DNA damage checkpoints. In general, DNA strand breaks appear to induce GI arrest, given a probability that replication does not occur until the repair is completed. Checkpoints at S and G2 phases, where the initiation of still inactive replicon clusters is delayed, prevent the entry of damaged cells into mitosis until the damage is repaired.

Inhibition of DNA repair and altered cell cycle progression and/or diminished cell cycle control, have been observed at low, non-cytotoxic concentrations of some metal compounds. Different metals such as Co (II) and Ni (II), elicited primarily G1 arrest, whereas arsenite caused G2 arrest. Some toxic metal compounds exert high affinities towards sulfhydryl groups and are potential targets for zinc finger proteins. These proteins are identified in several DNA damage repair enzymes, including mammalian Xeroderma Pigmentosum group A protein essential for damage recognition during NER and the bacterial formamido pyramidine-DNA (Fapy) glycosylase.

Arsenic is a well-recognized environmental contaminant. Exposure to arsenic is a worldwide public health problem. Recent identification of trivalent monomethyl arsonous acid and iododimethyl arsine in the urine from individuals ingesting arseniccontaminated drinking water suggests that the methylated trivalent arsenicals may be implicated in human toxicity after arsenic exposure. Although several modes of action have been suggested for arsenic genotoxicity and carcinogenicity, no single mode of action is widely accepted. However, aberrations in DNA repair leading to alterations in cell proliferation and/or apoptosis as a common mechanism across tissues seems like a very relevant testable hypothesis to study the mechanistic basis of arsenic-induced carcinogenicity. In addition, the presence of several compounding factors, such as UV, and other metals contribute to the complexity of its toxicity as well as its carcinogenicity. There is a wealth of information on the role of DNA repair and cell cycle regulation in arsenic-induced carcinogenesis. However, there is a dearth of details on mechanistic basis to arrive at unified, meaningful conclusions due to limitations of the relevant in vitro and in vivo models. Our recent studies with arsenicals in human primary keratinocytes indicate that these arsenicals overrode the growth arrest caused by UV and induced cell proliferation in a concentration dependent manner and resulted in significant change in the expression of cell cycle proteins such as PCNA, cyclin D and other early signaling enzymes. The role of these proteins in defending the cell against carcinogenic effects of arsenic will be discussed. (This abstract does not reflect EPA policy).DNA DAMAGE REPAIR AND CELL CYCLE CONTROL: A natural bio-defense mechanism
Anuradha Mudipalli.

Maintenance of genetic information, including the correct sequence of nucleotides in DNA, is essential for replication, gene expression, and protein synthesis. DNA lesions onto oncogenes or tumor suppressor genes may lead to cell cycle arrest, programmed cell death, mutagenesis, genomic instability and cancer. In addition to endogenous replication errors, DNA is also damaged by environmental mutagens such as UV light, polycyclic aromatic hydrocarbons (PAHs), and agents that induce reactive oxygen species (ROS) generated by oxygen metabolism. Diverse DNA repair systems have evolved to remove DNA lesions from endogenous and exogenous sources. DNA replication errors are corrected by mismatch repair systems, where mis-paired DNA bases are recognized and removed from the newly synthesized DNA strand shortly after DNA replication. Other spontaneous DNA alterations include deamination, hydrolysis, nonenzymatic methylation of DNA bases, and DNA damage induced by ROS. The spontaneous or chemicalinduced DNA lesions include, DNA single- and double- strand breaks, apurinic/apyrimidinic (AP) sites, DNA protein cross-links and DNA base modifications. Among these base modifications, 7,8-dihydro-8oxoguanine (8oxoguanine) is mutagenic by G-T transversions and thus may play an important role in carcinogenesis. Oxidative DNA lesions including strand breaks and AP sites as well as other types of DNA base alterations are eliminated by base excision repair (BER). DNA damage induced by environmental mutagens is also repaired by nucleotide excision repair (NER). NER is the most versatile repair system involved in the removal of structurally unrelated bulky adducts that cause significant helical distortions, including DNA damage induced by UV radiation and also more stable adducts formed by compounds like Benzo[a]pyrene. Lastly, DNA double strand breaks as well as DNA-DNA interstrand cross links induced, for example, by cytoplasmic platinum-based drugs are repaired by homologous or illegitimate recombination processes.

DNA damage, in addition to alerting the DNA repair processes, also regulates cell cycle progression by DNA damage checkpoints, which are highly interactive networks. These checkpoints, in general, control the cell's ability to arrest the cell cycle in response to DNA damage, regulate the activation of DNA repair pathways, the activation of a transcriptional program, and even programmed cell death (apoptosis) in the case of heavy damage. All these control mechanisms operate throughout the cell cycle and there are three important DNA damage checkpoints. In general, DNA strand breaks appear to induce GI arrest, given a probability that replication does not occur until the repair is completed. Checkpoints at S and G2 phases, where the initiation of still inactive replicon clusters is delayed, prevent the entry of damaged cells into mitosis until the damage is repaired.

Inhibition of DNA repair and altered cell cycle progression and/or diminished cell cycle control, have been observed at low, non-cytotoxic concentrations of some metal compounds. Different metals such as Co (II) and Ni (II), elicited primarily G1 arrest, whereas arsenite caused G2 arrest. Some toxic metal compounds exert high affinities towards sulfhydryl groups and are potential targets for zinc finger proteins. These proteins are identified in several DNA damage repair enzymes, including mammalian Xeroderma Pigmentosum group A protein essential for damage recognition during NER and the bacterial formamido pyramidine-DNA (Fapy) glycosylase.

Arsenic is a well-recognized environmental contaminant. Exposure to arsenic is a worldwide public health problem. Recent identification of trivalent monomethyl arsonous acid and iododimethyl arsine in the urine from individuals ingesting arseniccontaminated drinking water suggests that the methylated trivalent arsenicals may be implicated in human toxicity after arsenic exposure. Although several modes of action have been suggested for arsenic genotoxicity and carcinogenicity, no single mode of action is widely accepted. However, aberrations in DNA repair leading to alterations in cell proliferation and/or apoptosis as a common mechanism across tissues seems like a very relevant testable hypothesis to study the mechanistic basis of arsenic-induced carcinogenicity. In addition, the presence of several compounding factors, such as UV, and other metals contribute to the complexity of its toxicity as well as its carcinogenicity. There is a wealth of information on the role of DNA repair and cell cycle regulation in arsenic-induced carcinogenesis. However, there is a dearth of details on mechanistic basis to arrive at unified, meaningful conclusions due to limitations of the relevant in vitro and in vivo models. Our recent studies with arsenicals in human primary keratinocytes indicate that these arsenicals overrode the growth arrest caused by UV and induced cell proliferation in a concentration dependent manner and resulted in significant change in the expression of cell cycle proteins such as PCNA, cyclin D and other early signaling enzymes. The role of these proteins in defending the cell against carcinogenic effects of arsenic will be discussed. (This abstract does not reflect EPA policy).

Record Details:

Record Type:DOCUMENT( PRESENTATION/ ABSTRACT)
Product Published Date:08/09/2003
Record Last Revised:06/21/2006
Record ID: 66329