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

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

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

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

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

AIMTo investigate the prevalence of high levels of sperm DNA damage among men from infertile couples with both normal and abnormal standard semen parameters.

METHODSA total of 350 men from infertile couples were assessed. Standard semen analysis and sperm chromatin structure assay (SCSA) were carried out.

RESULTSNinety-seven men (28% of the whole study group) had a DNA fragmentation index (DFI)> 20%, and 43 men (12%) had a DFI>30%. In the group of men with abnormal semen parameters (n = 224), 35% had a DFI>20%, and 16% had a DFI>30%, whereas these numbers were 15% and 5%, respectively, in the group of men with normal semen parameters (n=126). Men with low sperm motility and abnormal morphology had significantly higher odds ratios (ORs) for having a DFI>20% (4.0 for motility and 1.9 for morphology) and DFI>30% (6.2 for motility and 2.8 for morphology) compared with men with normal sperm motility and morphology.

CONCLUSIONIn almost one-third of unselected men from infertile couples, the DFI exceeded the level of 20% above which, according to previous studies, the in vivo fertility is reduced. A significant proportion of men with otherwise normal semen parameters also had high sperm DNA damage levels. Thus, the SCSA test could add to explaining causes of infertility in cases where semen analysis has not shown any deviation from the norm. We also recommend running the SCSA test to choose the appropriate assisted reproductive technique (ART).

Chromatin ; pathology ; DNA Damage ; Female ; Humans ; Infertility, Male ; epidemiology ; genetics ; physiopathology ; Male ; Prevalence ; Semen ; cytology ; Spermatozoa ; physiology

BRCA1 is a well-established tumor suppressor gene, which is frequently mutated in familial breast and ovarian cancers. The gene product of BRCA1 functions in a number of cellular pathways that maintain genomic stability, including DNA damage-induced cell cycle checkpoint activation, DNA damage repair, protein ubiquitination, chromatin remodeling, as well as transcriptional regulation and apoptosis. In this review, we discuss recent advances regarding our understanding of the role of BRCA1 in tumor suppression and DNA damage response, including DNA damage-induced cell cycle checkpoint activation and DNA damage repair.
Apoptosis ; genetics ; BRCA1 Protein ; genetics ; physiology ; Breast Neoplasms ; genetics ; DNA Damage ; genetics ; DNA Repair ; genetics ; Female ; Genes, Tumor Suppressor ; Genes, cdc ; physiology ; Humans ; Mutation ; Ovarian Neoplasms ; genetics ; Signal Transduction ; genetics

OBJECTIVEThis review examines the evidence that: Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage; DNA damage can cause mutations; and DNA mutation is linked to carcinogenesis.

DATA SOURCESWe retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis.

STUDY SELECTIONWe included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes.

RESULTSThere are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification (i.e., oxidation). Emerging experimental data suggest that signal pathways (i.e., Akt/tuberin) link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk.

CONCLUSIONSThis review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer.

Animals ; DNA Damage ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; metabolism ; Humans ; Neoplasms ; genetics ; metabolism ; Oxidative Stress ; genetics ; physiology ; Reactive Oxygen Species ; metabolism

Sperm are a highly specialized cell type derived to deliver the paternal haploid genome to the oocyte. The epigenetic, or gene regulatory, properties and mechanisms of the sperm assist in preparation of the paternal genome to contribute to embryogenesis and the genome of the zygote. Many recent studies have addressed the issue of altered epigenetic processes in the sperm. This review evaluates the current understanding of DNA damage, chromosome aneuploidy, reduced telomere length, malformations of the centrosome, genomic imprinting errors, altered mRNA profiles, and abnormal nuclear packaging in the sperm prior to fertilization and the observed effects on embryogenesis. Attention has also been given to understanding the underlying etiology of sperm with altered epigenetic mechanisms in humans.
Aneuploidy ; Animals ; Cell Nucleus ; physiology ; Centrosome ; pathology ; DNA Damage ; physiology ; Embryonic Development ; physiology ; Epigenesis, Genetic ; Genomic Imprinting ; physiology ; Humans ; Infertility, Male ; genetics ; Male ; RNA, Messenger ; physiology ; Spermatozoa ; abnormalities ; physiology ; Telomere ; genetics