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Acta Biochimica Et Biophysica Sinica Sep 2019Double strand breaks (DSBs) are the most detrimental type of DNA damage that must be repaired to ensure genome integrity and cell survival. Unrepaired or improperly... (Review)
Review
Double strand breaks (DSBs) are the most detrimental type of DNA damage that must be repaired to ensure genome integrity and cell survival. Unrepaired or improperly repaired DSBs can potentially cause tumorigenesis or cell death. DSBs are primarily repaired by non-homologous end joining or homologous recombination (HR). The HR pathway is initiated by processing of the 5'-end of DSBs to generate 3'-end single-strand DNA (ssDNA). Furthermore, the intermediate is channeled to one of the HR sub-pathways, including: (i) double Holliday junction (dHJ) pathway, (ii) synthesis-dependent strand annealing (SDSA), (iii) break-induced replication (BIR), and (iv) single-strand annealing (SSA). In the dHJ sub-pathway, the 3'-ssDNA coated with Rad51 recombinase performs homology search and strand invasion, forming a displacement loop (D-loop). Capture of the second end by the D-loop generates a dHJ intermediate that is subsequently dissolved by DNA helicase or resolved by nucleases, producing non-crossover or crossover products. In SDSA, the newly synthesized strand is displaced from the D-loop and anneals to the end on the other side of the DSBs, producing non-crossovers. In contrast, BIR repairs one-end DSBs by copying the sequence up to the end of the template chromosome, resulting in translocation or loss of heterozygosity. SSA takes place when resection reveals flanking homologous repeats that can anneal, leading to deletion of the intervening sequences. A variety of reporter assays have been developed to monitor distinct HR sub-pathways in both Saccharomyces cerevisiae and mammals. Here, we summarize the principles and representative assays for different HR sub-pathways with an emphasis on the studies in the budding yeast.
Topics: Animals; DNA Breaks, Double-Stranded; DNA, Fungal; Genetic Techniques; Humans; Recombinational DNA Repair; Saccharomyces cerevisiae
PubMed: 31294447
DOI: 10.1093/abbs/gmz076 -
International Journal of Oral Science Oct 2011Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data... (Review)
Review
Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination (HR), are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; DNA Repair; Gene Expression Regulation, Neoplastic; Genes, Lethal; Genes, Tumor Suppressor; Genes, cdc; Humans; Mutagenesis; Poly(ADP-ribose) Polymerase Inhibitors; Rad52 DNA Repair and Recombination Protein; Recombination, Genetic
PubMed: 22010575
DOI: 10.4248/IJOS11064 -
Proceedings. Biological Sciences Sep 2016Meiosis is an ancestral, highly conserved process in eukaryotic life cycles, and for all eukaryotes the shared component of sexual reproduction. The benefits and... (Review)
Review
Meiosis is an ancestral, highly conserved process in eukaryotic life cycles, and for all eukaryotes the shared component of sexual reproduction. The benefits and functions of meiosis, however, are still under discussion, especially considering the costs of meiotic sex. To get a novel view on this old problem, we filter out the most conserved elements of meiosis itself by reviewing the various modifications and alterations of modes of reproduction. Our rationale is that the indispensable steps of meiosis for viability of offspring would be maintained by strong selection, while dispensable steps would be variable. We review evolutionary origin and processes in normal meiosis, restitutional meiosis, polyploidization and the alterations of meiosis in forms of uniparental reproduction (apomixis, apomictic parthenogenesis, automixis, selfing) with a focus on plants and animals. This overview suggests that homologue pairing, double-strand break formation and homologous recombinational repair at prophase I are the least dispensable elements, and they are more likely optimized for repair of oxidative DNA damage rather than for recombination. Segregation, ploidy reduction and also a biparental genome contribution can be skipped for many generations. The evidence supports the theory that the primary function of meiosis is DNA restoration rather than recombination.
Topics: Animals; Biological Evolution; Eukaryota; Meiosis; Plants; Recombination, Genetic; Reproduction
PubMed: 27605505
DOI: 10.1098/rspb.2016.1221 -
DNA Repair Jan 2021Homologous recombination (HR), considered the highest fidelity DNA double-strand break (DSB) repair pathway that a cell possesses, is capable of repairing multiple DSBs... (Review)
Review
Homologous recombination (HR), considered the highest fidelity DNA double-strand break (DSB) repair pathway that a cell possesses, is capable of repairing multiple DSBs without altering genetic information. However, in "last resort" scenarios, HR can be directed to low fidelity subpathways which often use non-allelic donor templates. Such repair mechanisms are often highly mutagenic and can also yield chromosomal rearrangements and/or deletions. While the choice between HR and its less precise counterpart, non-homologous end joining (NHEJ), has received much attention, less is known about how cells manage and prioritize HR subpathways. In this review, we describe work focused on how chromatin and nuclear architecture orchestrate subpathway choice and repair template usage to maintain genome integrity without sacrificing cell survival. Understanding the relationships between nuclear architecture and recombination mechanics will be critical to understand these cellular repair decisions.
Topics: Animals; Cell Nucleus; Chromatin; DNA End-Joining Repair; Eukaryota; Humans; Recombinational DNA Repair
PubMed: 33285474
DOI: 10.1016/j.dnarep.2020.103018 -
Cold Spring Harbor Perspectives in... Oct 2015The study of homologous recombination has its historical roots in meiosis. In this context, recombination occurs as a programmed event that culminates in the formation... (Review)
Review
The study of homologous recombination has its historical roots in meiosis. In this context, recombination occurs as a programmed event that culminates in the formation of crossovers, which are essential for accurate chromosome segregation and create new combinations of parental alleles. Thus, meiotic recombination underlies both the independent assortment of parental chromosomes and genetic linkage. This review highlights the features of meiotic recombination that distinguish it from recombinational repair in somatic cells, and how the molecular processes of meiotic recombination are embedded and interdependent with the chromosome structures that characterize meiotic prophase. A more in-depth review presents our understanding of how crossover and noncrossover pathways of meiotic recombination are differentiated and regulated. The final section of this review summarizes the studies that have defined defective recombination as a leading cause of pregnancy loss and congenital disease in humans.
Topics: Chromosomes; Crossing Over, Genetic; DNA; DNA Breaks, Double-Stranded; Endonucleases; Female; Humans; Maternal Age; Meiosis; Models, Genetic; Recombination, Genetic; Reproduction
PubMed: 26511629
DOI: 10.1101/cshperspect.a016618 -
Trends in Genetics : TIG Jul 2018Break-induced replication (BIR) is a pathway that repairs one-ended double-strand breaks (DSBs). For decades, yeast model systems offered the only opportunities to study... (Review)
Review
Break-induced replication (BIR) is a pathway that repairs one-ended double-strand breaks (DSBs). For decades, yeast model systems offered the only opportunities to study eukaryotic BIR. These studies described an unusual mode of BIR synthesis that is carried out by a migrating bubble and shows conservative inheritance of newly synthesized DNA, leading to genomic instabilities like those associated with cancer in humans. Yet, evidence of BIR functioning in mammals or during repair of other DNA breaks has been missing. Recent studies have uncovered multiple examples of BIR working in replication restart and repair of eroded telomeres in yeast and mammals, as well as some unexpected findings, including the RAD51 independence of BIR. Strong interest remains in determining the variations in molecular mechanisms that drive and regulate BIR in different genetic backgrounds, across organisms, and particularly in the context of human disease.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Genomic Instability; Humans; Recombination, Genetic; Telomere
PubMed: 29735283
DOI: 10.1016/j.tig.2018.04.002 -
Breast Cancer Research : BCR 2001Two recent papers provide new evidence relevant to the role of the breast cancer susceptibility gene BRCA2 in DNA repair. Moynahan et al provide genetic data indicating... (Review)
Review
Two recent papers provide new evidence relevant to the role of the breast cancer susceptibility gene BRCA2 in DNA repair. Moynahan et al provide genetic data indicating a requirement for BRCA2 in homology-dependent (recombinational) repair of DNA double-strand breaks. The second paper, by Davies et al, begins to address the mechanism through which BRCA2 makes its contribution to recombinational repair. BRCA2 appears to function in recombination via interactions with the major eukaryotic recombinase RAD51 [1,2,3]. We briefly review the context in which the two studies were carried out, we comment on the results presented, and we discuss models designed to account for the role of BRCA2 in RAD51-mediated repair.
Topics: BRCA2 Protein; Breast Neoplasms; DNA Repair; DNA-Binding Proteins; Female; Humans; Neoplasm Proteins; Rad51 Recombinase; Recombination, Genetic; Transcription Factors
PubMed: 11597317
DOI: 10.1186/bcr310 -
Molecules and Cells May 2022During meiosis, homologous chromosomes (homologs) pair and undergo genetic recombination via assembly and disassembly of the synaptonemal complex. Meiotic recombination... (Review)
Review
During meiosis, homologous chromosomes (homologs) pair and undergo genetic recombination via assembly and disassembly of the synaptonemal complex. Meiotic recombination is initiated by excess formation of DNA double-strand breaks (DSBs), among which a subset are repaired by reciprocal genetic exchange, called crossovers (COs). COs generate genetic variations across generations, profoundly affecting genetic diversity and breeding. At least one CO between homologs is essential for the first meiotic chromosome segregation, but generally only one and fewer than three inter-homolog COs occur in plants. CO frequency and distribution are biased along chromosomes, suppressed in centromeres, and controlled by pro-CO, anti-CO, and epigenetic factors. Accurate and high-throughput detection of COs is important for our understanding of CO formation and chromosome behavior. Here, we review advanced approaches that enable precise measurement of the location, frequency, and genomic landscapes of COs in plants, with a focus on .
Topics: Arabidopsis; Crossing Over, Genetic; DNA Breaks, Double-Stranded; Homologous Recombination; Meiosis; Plants
PubMed: 35444069
DOI: 10.14348/molcells.2022.2054 -
Biochemical Society Transactions Feb 2024Meiotic recombination, a cornerstone of eukaryotic diversity and individual genetic identity, is essential for the creation of physical linkages between homologous... (Review)
Review
Meiotic recombination, a cornerstone of eukaryotic diversity and individual genetic identity, is essential for the creation of physical linkages between homologous chromosomes, facilitating their faithful segregation during meiosis I. This process requires that germ cells generate controlled DNA lesions within their own genome that are subsequently repaired in a specialised manner. Repair of these DNA breaks involves the modulation of existing homologous recombination repair pathways to generate crossovers between homologous chromosomes. Decades of genetic and cytological studies have identified a multitude of factors that are involved in meiotic recombination. Recent work has started to provide additional mechanistic insights into how these factors interact with one another, with DNA, and provide the molecular outcomes required for a successful meiosis. Here, we provide a review of the recent developments with a focus on protein structures and protein-protein interactions.
Topics: DNA Breaks, Double-Stranded; Homologous Recombination; DNA Repair; Meiosis; Chromosomes
PubMed: 38348856
DOI: 10.1042/BST20230712 -
DNA Repair Aug 2017Replication forks frequently are challenged by lesions on the DNA template, replication-impeding DNA secondary structures, tightly bound proteins or nucleotide pool... (Review)
Review
Replication forks frequently are challenged by lesions on the DNA template, replication-impeding DNA secondary structures, tightly bound proteins or nucleotide pool imbalance. Studies in bacteria have suggested that under these circumstances the fork may leave behind single-strand DNA gaps that are subsequently filled by homologous recombination, translesion DNA synthesis or template-switching repair synthesis. This review focuses on the template-switching pathways and how the mechanisms of these processes have been deduced from biochemical and genetic studies. I discuss how template-switching can contribute significantly to genetic instability, including mutational hotspots and frequent genetic rearrangements, and how template-switching may be elicited by replication fork damage.
Topics: Bacteria; DNA Repair; DNA Replication; DNA, Bacterial; Recombinational DNA Repair
PubMed: 28641943
DOI: 10.1016/j.dnarep.2017.06.014