The Role of DNA Repair and the Epigenetic Markers Left after Repair in Neurologic Functions, Including Memory and Learning
In eukaryotic cell nuclei, DNA is wrapped around and firmly associated with histone proteins, forming chromatin. When DNA is damaged, the chromatin structure needs to be loosened to allow repair enzymes to gain access to the damage. This requires modifying the histone proteins. These modifications, called epigenetic alterations, do not alter the base-pair sequence. Repair-associated epigenetic alterations are usually transient, removed when no longer needed for repair. However, some remain after repair. In the human brain, long-lasting novel epigenetic alterations appear to account for the persistence of addictions to such substances as alcohol, nicotine and cocaine. Certain neurodegenerative diseases are caused by inherited mutations in genes necessary for DNA repair. Deficient DNA repair in these diseases is associated with extensive epigenetic alterations that likely have a role in the disease phenotype. Persistent epigenetic alterations due to DNA repair processes, both histone modifications and methylations of DNA, can also have positive consequences. Stimulation of brain activity (e.g. learning and memory formation) is often accompanied by the generation of DNA damage in neuronal DNA, followed by repair associated with persistent epigenetic alterations. In particular, recent research has shown the need for non-homologous end joining and base excision repair in memory formation.
Part of the book: DNA Repair
Sexual Processes in Microbial Eukaryotes
Two principal ideas have been proposed to explain the primary adaptive function of the sexual process of meiosis: (1) meiosis, and particularly meiotic recombination, is a process for repairing DNA and (2) meiosis, by means of meiotic recombination, is a process for generating beneficial genetic variation among progeny. We review the sexual processes of a number of well-studied microbial eukaryotes: Saccharomyces cerevisiae, Saccharomyces paradoxus, Schizosaccharomyces pombe, Candida albicans, Ustilago maydis, Paramecium tetraurelia, Volvox carteri, Trypanosoma brucei, Neurospora crassa, and Amoebozoa. We indicate aspects of the sexual processes of these microbial eukaryotes, where they have been established, that support the idea that meiosis is primarily a process for repairing DNA. In addition, we review the likely origin of meiotic sex among the microbial eukaryotes. A prokaryotic archaeon is the likely ancestor of eukaryotes. Extant archaea are capable of a sexual process involving syngamy and recombinational repair of genome damage, suggesting that the precursor of eukaryotic meiotic sex may already have been present in the archaeal ancestor of eukaryotes. We believe that attainment of an understanding of the adaptive function of meiotic sex in microbial eukaryotes is of considerable importance since it will likely apply to meiotic sex in eukaryotes generally.
Part of the book: Parasitology and Microbiology Research
Demethylation in Early Embryonic Development and Memory
DNA repair processes arose early in evolution. During evolution, DNA base excision repair apparently acquired additional roles in demethylation of cytosines in DNA. Demethylation is central to two mammalian fundamental processes. Embryonic reprogramming and neuronal memory require rapid gene expression alterations depending in part on demethylations. The active demethylation reactions in both processes primarily depend, first, on the family of 5-methylcytosine oxidases sharing the acronym ten-eleven translocation (TET methylcytosine dioxygenases) and, second, on DNA base excision repair enzymes. In mice, within 6 h of fertilization, the paternal chromosomes are close to 100% actively demethylated through TET and repair activity. (Methylation of maternal DNA is blocked during subsequent cycles of replication, so methyl groups on maternal DNA, passively, becomes highly diluted over the next 4 days.) Rats subjected to one instance of contextual fear conditioning create an especially strong long-term memory. At 24 h after training, 9.2% of the genes in the rat genomes of hippocampus neurons are differentially methylated, including over 500 genes with demethylation. The emergence of embryonic development in evolution depended on preexisting DNA methylation/demethylation pathways to modify gene expression. The further emergence of memory likely evolved from the earlier set of methylation/demethylation capabilities associated with embryonic development.
Part of the book: DNA Methylation Mechanism
Origin of DNA Repair in the RNA WorldView all chapters
The early history of life on Earth likely included a stage in which life existed as self-replicating protocells with single-stranded RNA (ssRNA) genomes. In this RNA world, genome damage from a variety of sources (spontaneous hydrolysis, UV, etc.) would have been a problem for survival. Selection pressure for dealing with genome damage would have led to adaptive strategies for mitigating the damage. In today’s world, RNA viruses with ssRNA genomes are common, and these viruses similarly need to cope with genome damage. Thus ssRNA viruses can serve as models for understanding the early evolution of genome repair. As the ssRNA protocells in the early RNA world evolved, the RNA genome likely gave rise, through a series of evolutionary stages, to the double-stranded DNA (dsDNA) genome. In ssRNA to dsDNA evolution, genome repair processes also likely evolved to accommodate this transition. Some of the basic features of ssRNA genome repair appear to have been retained in descendants with dsDNA genomes. In particular, a type of strand-switching recombination occurs when ssRNA replication is blocked by a damage in the template strand. Elements of this process appear to have a central role in recombinational repair processes during meiosis and mitosis of descendant dsDNA organisms.
Part of the book: DNA