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DNA Repair Sep 2015Both p53 and BRCA1 are tumor suppressors and are involved in a number of cellular processes including cell cycle arrest, apoptosis, transcriptional regulation, and DNA...
Both p53 and BRCA1 are tumor suppressors and are involved in a number of cellular processes including cell cycle arrest, apoptosis, transcriptional regulation, and DNA damage repair. Some studies have suggested that the association of BRCA1 and p53 is required for transcriptional regulation of genes involved in cell replication and DNA repair pathways. However, the relationship between the two proteins in molecular mechanisms of DNA repair is still not clear. Therefore, we sought to determine whether there is a functional link between p53 and BRCA1 in DNA repair. Firstly, using a plasmid recombination substrate, pDR-GFP, integrated into the genome of breast cancer cell line MCF7, we have demonstrated that p53 suppressed Rad51-mediated hyper-recombinational repair by two independent cell models of HPV-E6 induced p53 inactivation and p53 knockdown assay. Our study further indicated that p53 mediated homologous recombination (HR) through inhibiting BRCA1 over-function via mechanism of transcription regulation in response to DNA repair. Since it was found p53 and BRCA1 existed in a protein complex, indicating both proteins may be associated at post-transcriptional level. Moreover, defective p53-induced hyper-recombination was associated with cell radioresistance and chromosomal stability, strongly supporting the involvement of p53 in the inhibition of hyper-recombination, which led to genetic stability and cellular function in response to DNA damage. In addition, it was found that p53 loss rescued BRCA1 deficiency via recovering HR and chromosomal stability, suggesting that p53 is also involved in the HR-inhibition independently of BRCA1. Thus, our data indicated that p53 was involved in inhibiting recombination by both BRCA1-dependent and -independent mechanisms, and there is a functional link between p53-suppression and BRCA1-promotion in regulation of HR activity at transcription level and possible post-transcription level.
Topics: BRCA1 Protein; Cell Line, Tumor; Chromosomal Instability; DNA Damage; Humans; Rad51 Recombinase; Radiation, Ionizing; Recombination, Genetic; Transcription, Genetic; Tumor Suppressor Protein p53
PubMed: 26162908
DOI: 10.1016/j.dnarep.2015.06.005 -
JCO Precision Oncology May 2022Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types,...
PURPOSE
Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, / alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated.
METHODS
We obtained data sets of all solid tumors in The Cancer Genome Atlas and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, per-sample genomic scar scores, ie, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic mutations, sex, and clinical information including chemotherapeutic regimens.
RESULTS
Biallelic alterations in HRR genes other than / were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic mutations. HRD cases determined by a combination of these indices also showed HRD features in gene expression analysis and were associated with better survival when treated with DNA-damaging agents.
CONCLUSION
This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.
Topics: Biomarkers; Cicatrix; Female; Humans; Male; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Precision Medicine; Recombinational DNA Repair
PubMed: 35613413
DOI: 10.1200/PO.22.00085 -
Cellular and Molecular Life Sciences :... Mar 2009DNA double-strand breaks (DSBs) arise in cells from endogenous and exogenous attacks on the DNA backbone, but also as a direct consequence of replication failures.... (Review)
Review
DNA double-strand breaks (DSBs) arise in cells from endogenous and exogenous attacks on the DNA backbone, but also as a direct consequence of replication failures. Proper repair of all these DSBs is essential for genome stability. Repair of broken chromosomes is a challenge for dividing cells that need to distribute equal genetic information to daughter cells. Consequently, eukaryotic organisms have evolved multi-potent and efficient mechanisms to repair DSBs that are primarily divided into two types of pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR). Here we briefly describe how eukaryotic cells sense DSBs and trigger cell cycle arrest to allow repair, and we review the mechanisms of both NHEJ and HR pathways and the choice between them. (Part of a Multi-author Review).
Topics: Cell Cycle; DNA Breaks, Double-Stranded; DNA Damage; DNA Ligases; DNA Repair; DNA Replication; Genomic Instability; Recombination, Genetic
PubMed: 19153654
DOI: 10.1007/s00018-009-8740-3 -
BioEssays : News and Reviews in... Nov 2012Gradual degradation seems inevitable for non-recombining sex chromosomes. This has been supported by the observation of degenerated non-recombining sex chromosomes in a... (Review)
Review
Gradual degradation seems inevitable for non-recombining sex chromosomes. This has been supported by the observation of degenerated non-recombining sex chromosomes in a variety of species. The human Y chromosome has also degenerated significantly during its evolution, and theories have been advanced that the Y chromosome could disappear within the next ~5 million years, if the degeneration rate it has experienced continues. However, recent studies suggest that this is unlikely. Conservative evolutionary forces such as strong purifying selection and intrachromosomal repair through gene conversion balance the degeneration tendency of the Y chromosome and maintain its integrity after an initial period of faster degeneration. We discuss the evidence both for and against the extinction of the Y chromosome. We also discuss potential insights gained on the evolution of sex-determining chromosomes by studying simpler sex-determining chromosomal regions of unicellular and multicellular microorganisms.
Topics: Animals; Bacteria; Chromosomes, Human, Y; Evolution, Molecular; Genetic Loci; Humans; Recombination, Genetic; Y Chromosome
PubMed: 22948853
DOI: 10.1002/bies.201200064 -
Science China. Life Sciences Mar 2015Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. During meiosis homologous... (Review)
Review
Meiotic recombination is a deeply conserved process within eukaryotes that has a profound effect on patterns of natural genetic variation. During meiosis homologous chromosomes pair and undergo DNA double strand breaks generated by the Spo11 endonuclease. These breaks can be repaired as crossovers that result in reciprocal exchange between chromosomes. The frequency of recombination along chromosomes is highly variable, for example, crossovers are rarely observed in heterochromatin and the centromeric regions. Recent work in plants has shown that crossover hotspots occur in gene promoters and are associated with specific chromatin modifications, including H2A.Z. Meiotic chromosomes are also organized in loop-base arrays connected to an underlying chromosome axis, which likely interacts with chromatin to organize patterns of recombination. Therefore, epigenetic information exerts a major influence on patterns of meiotic recombination along chromosomes, genetic variation within populations and evolution of plant genomes.
Topics: Chromatin; Crossing Over, Genetic; Epigenesis, Genetic; Meiosis; Plants; Recombination, Genetic
PubMed: 25651968
DOI: 10.1007/s11427-015-4811-x -
FEBS Letters Apr 2017DNA amplification is a powerful mutational mechanism that is a hallmark of cancer and drug resistance. It is therefore important to understand the fundamental pathways... (Review)
Review
DNA amplification is a powerful mutational mechanism that is a hallmark of cancer and drug resistance. It is therefore important to understand the fundamental pathways that cells employ to avoid over-replicating sections of their genomes. Recent studies demonstrate that, in the absence of RecG, DNA amplification is observed at sites of DNA double-strand break repair (DSBR) and of DNA replication arrest that are processed to generate double-strand ends. RecG also plays a role in stabilising joint molecules formed during DSBR. We propose that RecG prevents a previously unrecognised mechanism of DNA amplification that we call reverse-restart, which generates DNA double-strand ends from incorrect loading of the replicative helicase at D-loops formed by recombination, and at arrested replication forks.
Topics: Animals; Bacterial Proteins; DNA Breaks, Double-Stranded; DNA Helicases; DNA Repair; DNA Replication; Endodeoxyribonucleases; Escherichia coli; Escherichia coli Proteins; Gene Amplification; Humans; Models, Biological; Protein Multimerization; Recombination, Genetic; Recombinational DNA Repair
PubMed: 28155219
DOI: 10.1002/1873-3468.12583 -
The Journal of Biological Chemistry Aug 2004The repair of psoralen interstrand cross-links in the yeast Saccharomyces cerevisiae involves the DNA repair groups nucleotide excision repair (NER), homologous...
The repair of psoralen interstrand cross-links in the yeast Saccharomyces cerevisiae involves the DNA repair groups nucleotide excision repair (NER), homologous recombination (HR), and post-replication repair (PRR). In repair-proficient yeast cells cross-links induce double-strand breaks, in an NER-dependent process; the double-strand breaks are then repaired by HR. An alternate error-prone repair pathway generates mutations at cross-link sites. We have characterized the repair of plasmid molecules carrying a single psoralen cross-link, psoralen monoadduct, or double-strand break in yeast cells with deficiencies in NER, HR, or PRR genes, measuring the repair efficiencies and the levels of gene conversions, crossing over, and mutations. Strains with deficiencies in the NER genes RAD1, RAD3, RAD4, and RAD10 had low levels of cross-link-induced recombination but higher mutation frequencies than repair-proficient cells. Deletion of the HR genes RAD51, RAD52, RAD54, RAD55, and RAD57 also decreased induced recombination and increased mutation frequencies above those of NER-deficient yeast. Strains lacking the PRR genes RAD5, RAD6, and RAD18 did not have any cross-link-induced mutations but showed increased levels of recombination; rad5 and rad6 cells also had altered patterns of cross-link-induced gene conversion in comparison with repair-proficient yeast. Our observations suggest that psoralen cross-links can be repaired by three pathways: an error-free recombinational pathway requiring NER and HR and two PRR-dependent error-prone pathways, one NER-dependent and one NER-independent.
Topics: Alleles; Cross-Linking Reagents; DNA; DNA Damage; DNA Repair; DNA, Fungal; Ficusin; Models, Biological; Models, Genetic; Mutagenesis; Mutation; Phenotype; Plasmids; Recombination, Genetic; Saccharomyces cerevisiae
PubMed: 15213235
DOI: 10.1074/jbc.M402323200 -
Advances in Virus Research 1994It is well known that DNA-based organisms rearrange and repair their genomic DNA through recombination processes, and that these rearrangements serve as a powerful... (Review)
Review
It is well known that DNA-based organisms rearrange and repair their genomic DNA through recombination processes, and that these rearrangements serve as a powerful source of variability and adaptation for these organisms. In RNA viruses' genetic recombination is defined as any process leading to the exchange of information between viral RNAs. There are two types of recombination events: legitimate and illegitimate. While legitimate (homologous) recombination occurs between closely related sequences at corresponding positions, illegitimate (nonhomologous) recombination could happen at any position among the unrelated RNA molecules. In order to differentiate between the symmetrical and asymmetrical homologous crosses, Lai defined the former as homologous recombination and the latter as aberrant homologous recombination. This chapter uses brome mosaic virus (BMV), a multicomponent plant RNA virus, as an example to discuss the progress in studying the mechanism of genetic recombination in positive-stranded RNA viruses. Studies described in this chapter summarize the molecular approaches used to increase the frequency of recombination among BMV RNA segments and, more importantly, to target the sites of crossovers to specific BMV RNA regions. It demonstrates that the latter can be accomplished by introducing local complementarities to the recombining substrates.
Topics: Animals; Base Sequence; Bromovirus; Models, Genetic; Molecular Sequence Data; RNA, Viral; Recombination, Genetic; Viruses
PubMed: 8191956
DOI: 10.1016/s0065-3527(08)60051-2 -
Annual Review of Genetics Nov 2016Meiosis, the mechanism of creating haploid gametes, is a complex cellular process observed across sexually reproducing organisms. Fundamental to meiosis is the process... (Review)
Review
Meiosis, the mechanism of creating haploid gametes, is a complex cellular process observed across sexually reproducing organisms. Fundamental to meiosis is the process of homologous recombination, whereby DNA double-strand breaks are introduced into the genome and are subsequently repaired to generate either noncrossovers or crossovers. Although homologous recombination is essential for chromosome pairing during prophase I, the resulting crossovers are critical for maintaining homolog interactions and enabling accurate segregation at the first meiotic division. Thus, the placement, timing, and frequency of crossover formation must be exquisitely controlled. In this review, we discuss the proteins involved in crossover formation, the process of their formation and designation, and the rules governing crossovers, all within the context of the important landmarks of prophase I. We draw together crossover designation data across organisms, analyze their evolutionary divergence, and propose a universal model for crossover regulation.
Topics: Aneuploidy; Animals; Crossing Over, Genetic; DNA Breaks, Double-Stranded; DNA Repair; Meiosis; Meiotic Prophase I; Protein Processing, Post-Translational; Recombination, Genetic; Synaptonemal Complex
PubMed: 27648641
DOI: 10.1146/annurev-genet-120215-035111 -
Nature Communications Mar 2018Genetic studies in yeast indicate that RNA transcripts facilitate homology-directed DNA repair in a manner that is dependent on RAD52. The molecular basis for so-called...
Genetic studies in yeast indicate that RNA transcripts facilitate homology-directed DNA repair in a manner that is dependent on RAD52. The molecular basis for so-called RNA-DNA repair, however, remains unknown. Using reconstitution assays, we demonstrate that RAD52 directly cooperates with RNA as a sequence-directed ribonucleoprotein complex to promote two related modes of RNA-DNA repair. In a RNA-bridging mechanism, RAD52 assembles recombinant RNA-DNA hybrids that coordinate synapsis and ligation of homologous DNA breaks. In an RNA-templated mechanism, RAD52-mediated RNA-DNA hybrids enable reverse transcription-dependent RNA-to-DNA sequence transfer at DNA breaks that licenses subsequent DNA recombination. Notably, we show that both mechanisms of RNA-DNA repair are promoted by transcription of a homologous DNA template in trans. In summary, these data elucidate how RNA transcripts cooperate with RAD52 to coordinate homology-directed DNA recombination and repair in the absence of a DNA donor, and demonstrate a direct role for transcription in RNA-DNA repair.
Topics: DNA Breaks, Double-Stranded; DNA Repair; RNA; Rad52 DNA Repair and Recombination Protein; Recombinational DNA Repair; Saccharomyces cerevisiae Proteins
PubMed: 29545568
DOI: 10.1038/s41467-018-03483-7