Animals ; Cricetinae ; DNA Damage ; physiology ; Genes, p53 ; physiology ; Humans ; Mice ; Signal Transduction ; physiology

The damage to sperm DNA is one of the most important causes of male infertility. Some sperm with damaged DNA may escape from the sperm surveillance mechanism and transmit the damage to the offspring. So research on the damage to sperm DNA has become one of the hot spots in reproductive medicine. The factors that would damage sperm DNA include oxidative stress, microelements, reproductive toxic substances, radioactive rays, and so on, while the body depends on the compressed sperm DNA and anti-oxidation system for the protection of the integrity of sperm DNA. Some drugs such as anti-oxidant, black tea extract, etc, may help to improve and rebuild these protective mechanisms.
Antioxidants ; pharmacology ; DNA Damage ; DNA Repair ; physiology ; Humans ; Male ; Oxidative Stress ; Spermatozoa ; chemistry ; ultrastructure

The controlled generation of very low amounts of reactive oxygen species (ROS) appears to regulate normal sperm functions, while high levels of ROS endanger sperm viability and function. Oxidative stress (OS) develops as a consequence of excessive production of ROS and/or impaired antioxidant defense system. It is proposed that such OS precipitates a range of pathologies currently thought to afflict male reproductive function. ROS-mediated peroxidative damage to the sperm plasma membrane may account for defective sperm function observed in a high proportion of infertility patients. Excessive generation of ROS may also attack integrity of DNA in the sperm nucleus. DNA bases are susceptible to oxidative stress, and peroxidation of these structures can cause base modification, DNA strand breaks and chromatin cross-linking. DNA damage induced by excessive ROS may accelerate the process of germ cell apoptosis, leading to decline in sperm counts associated with male infertility, and may explain the apparent deterioration of semen quality observed during the past four to five decades. For almost a decade, our research team in the Cleveland Clinic Foundation has identified the critical role of OS in male infertility. The main objective of our research was to transfer this important knowledge from the research bench to clinical practice. We designed studies with the aims of: 1. understanding the exact mechanisms by which OS develops in semen, which we thought will help setup strategies to overcome the problem, 2. establishing assays for accurate assessment of OS status and running the quality control studies for this purpose, 3. testing the correlation between OS and sperm nuclear DNA damage, and 4. identifying the clinical significance of seminal OS assessment in male infertility practice.
DNA ; metabolism ; DNA Damage ; Humans ; Infertility, Male ; genetics ; metabolism ; Male ; Oxidative Stress ; physiology ; Reactive Oxygen Species ; metabolism ; Spermatozoa ; physiology

As an important telomere binding protein, TPP1 protects the ends of telomeres and maintains the stability and integrity of its structure and function by interacting with other five essential core proteins (POT1, TRF1, TRF2, TIN2, and RAP1) to form a complex called Shelterin. Recently, researchers have discovered that TPP1 participates in protection of telomeres and regulation of telomerase activity. The relationship between TPP1 and tumorigenesis, tumor progression and treatment has also been investigated. This paper reviews the latest findings of TPP1 regarding to its structure, function and interaction with other proteins involved in tumorigenesis.
Chromosomal Instability ; DNA Damage ; Humans ; Neoplasms ; genetics ; Telomere ; Telomere-Binding Proteins ; chemistry ; physiology

Nowadays, the injury in human mitochondrial DNA (mtDNA) is well known to accumulate in various tissues with age. It's significant to further investigate and then apply it to estimation of the age at parenchymas.
Aging/physiology* ; Base Pair Mismatch/genetics* ; DNA Damage/physiology* ; DNA Fragmentation/genetics* ; DNA, Mitochondrial/physiology* ; Gene Deletion ; Humans ; Polymerase Chain Reaction

Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatin-binding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.
Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism/*physiology ; DNA Damage/genetics/*physiology ; DNA Repair/genetics/*physiology ; Humans ; Mice ; Models, Biological ; Neoplasms/*genetics ; Nerve Tissue Proteins/genetics/metabolism/*physiology

Mammalian cells are frequently at risk of DNA damage from both endogenous and exogenous sources. Accordingly, cells have evolved the DNA damage response (DDR) pathways to monitor and assure the integrity of their genome. In cells, the intact and effective DDR is essential for the maintenance of genomic stability and it acts as a critical barrier to suppress the development of cancer in humans. Two central kinases for the DDR pathway are ATM and ATR, which can phosphorylate and activate many downstream proteins for cell cycle arrest, DNA repair, or apoptosis if the damages are irreparable. In the last several years, we and others have made significant progress to this field by identifying BRIT1 (also known as MCPH1) as a novel key regulator in the DDR pathway. BRIT1 protein contains 3 breast cancer carboxyl terminal (BRCT) domains which are conserved in BRCA1, MDC1, 53BP1, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. Our in vitro studies revealed BRIT1 to be a chromatin-binding protein required for recruitment of many important DDR proteins (ATM, MDC1, NBS1, RAD51, BRCA2) to the DNA damage sites. We recently also generated the BRIT1 knockout mice and demonstrated its essential roles in homologous recombination DNA repair and in maintaining genomic stability in vivo. In humans, BRIT1 is located on chromosome 8p23.1, where loss of hetero-zigosity is very common in many types of cancer. In this review, we will summarize the novel roles of BRIT1 in DDR, describe the relationship of BRIT1 deficiency with cancer development, and also discuss the use of synthetic lethality approach to target cancers with HR defects due to BRIT1 deficiency.
Animals ; Chromosomal Proteins, Non-Histone/genetics/metabolism/*physiology ; DNA Damage/genetics/*physiology ; DNA Repair/genetics/*physiology ; Humans ; Mice ; Models, Biological ; Neoplasms/*genetics ; Nerve Tissue Proteins/genetics/metabolism/*physiology

A common DNA polymerase can replicate DNA which functions normally. However, if DNA suffers damage, the genome can not be replicated by a common DNA polymerase because DNA lesions will block the replication apparatus. Another kind of DNA polymerases in organism, Y-family DNA polymerases which is also called translesion synthesis (TLS) polymerases, can deal with this problem. Their main functions are bypassing the lesions in DNA, replicating the genome and saving the dying cells. This thesis presents a historical review of the literature pertinent to the structure, functions and roles of Y-family DNA polymerases.
DNA Damage ; DNA Repair ; DNA Replication ; DNA-Directed DNA Polymerase ; classification ; metabolism ; physiology ; Humans ; Mutagenesis ; Mutagens ; Proliferating Cell Nuclear Antigen ; genetics

Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving "sensor" proteins that sense the damage, and transmit signals to "transducer" proteins, which, in turn, convey the signals to numerous "effector" proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.
Animals ; Apoptosis ; Cell Cycle ; Cellular Senescence ; DNA Damage ; DNA Methylation ; Genes, bcl-2 ; Humans ; Tumor Suppressor Protein p53 ; physiology

AIMTo explore the influence of cold strss on DNA oxidative damage of lung in chicken.

METHODSTook 15-day-old healthy chicks as the experimental object, carried on the cold stress (12 +/- 1 degrees C) to process. Detected the change of the MDA content, SOD and GSH-Px activity of the lung, and performed KCl-SDS precipitation method and fluorescence detection method to identify the influence of cold strss on DNA-protein crosslinks (DPC) and DNA-DNA crosslinks (DDC) of lung cell in different time.

RESULTSThe results were as follow: with the time lapsing during acute cold stress, MDA content gradually increased, the SOD and GSH-Px activity of the lung increased compared with their control group at each stress time point, and the lung cell DPC and DDC coefficient were all gradually increased with the time lapsing.

CONCLUSIONCold stress could bring about destruction in the lung tissue oxidation-antioxidant balance, and causes the oxidation damage of DNA.

Animals ; Animals, Newborn ; Chickens ; Cold Temperature ; DNA Damage ; Lung ; pathology ; Male ; Oxidative Stress ; physiology ; Stress, Physiological ; physiology