scholarly journals Structure-Specific Endonucleases and the Resolution of Chromosome Underreplication

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 232 ◽  
Author(s):  
Benoît Falquet ◽  
Ulrich Rass
Keyword(s):  
Sister Chromatid ◽  
Replication Fork ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Chromosome Breakage ◽  
Repair Synthesis ◽  
Daughter Cells ◽  
Oncogene Activation ◽  
Dna Repair Synthesis ◽  
Replication Intermediates

Complete genome duplication in every cell cycle is fundamental for genome stability and cell survival. However, chromosome replication is frequently challenged by obstacles that impede DNA replication fork (RF) progression, which subsequently causes replication stress (RS). Cells have evolved pathways of RF protection and restart that mitigate the consequences of RS and promote the completion of DNA synthesis prior to mitotic chromosome segregation. If there is entry into mitosis with underreplicated chromosomes, this results in sister-chromatid entanglements, chromosome breakage and rearrangements and aneuploidy in daughter cells. Here, we focus on the resolution of persistent replication intermediates by the structure-specific endonucleases (SSEs) MUS81, SLX1-SLX4 and GEN1. Their actions and a recently discovered pathway of mitotic DNA repair synthesis have emerged as important facilitators of replication completion and sister chromatid detachment in mitosis. As RS is induced by oncogene activation and is a common feature of cancer cells, any advances in our understanding of the molecular mechanisms related to chromosome underreplication have important biomedical implications.

scholarly journals Overcoming a nucleosomal barrier to replication

2016 ◽  
Vol 2 (11) ◽  
pp. e1601865 ◽  
Author(s):  
Han-Wen Chang ◽  
Manjula Pandey ◽  
Olga I. Kulaeva ◽  
Smita S. Patel ◽  
Vasily M. Studitsky
Keyword(s):  
Dna Polymerase ◽  
Replication Fork ◽  
Molecular Mechanisms ◽  
Normal Functioning ◽  
Daughter Cells ◽  
Nucleosomal Dna ◽  
Dna Loop ◽  
Rate Of Progression ◽  
Alternative Conformation

Efficient overcoming and accurate maintenance of chromatin structure and associated histone marks during DNA replication are essential for normal functioning of the daughter cells. However, the molecular mechanisms of replication through chromatin are unknown. We have studied traversal of uniquely positioned mononucleosomes by T7 replisome in vitro. Nucleosomes present a strong, sequence-dependent barrier for replication, with particularly strong pausing of DNA polymerase at the +(31–40) and +(41–65) regions of the nucleosomal DNA. The exonuclease activity of T7 DNA polymerase increases the overall rate of progression of the replisome through a nucleosome, likely by resolving nonproductive complexes. The presence of nucleosome-free DNA upstream of the replication fork facilitates the progression of DNA polymerase through the nucleosome. After replication, at least 50% of the nucleosomes assume an alternative conformation, maintaining their original positions on the DNA. Our data suggest a previously unpublished mechanism for nucleosome maintenance during replication, likely involving transient formation of an intranucleosomal DNA loop.

scholarly journals Palindromes in DNA—A Risk for Genome Stability and Implications in Cancer

2021 ◽  
Vol 22 (6) ◽  
pp. 2840
Author(s):  
Marina Svetec Miklenić ◽  
Ivan Krešimir Svetec
Keyword(s):  
Human Genome ◽  
Genome Stability ◽  
Molecular Mechanisms ◽  
Genetic Recombination ◽  
Chromosome Breakage ◽  
Fragile Sites ◽  
Cis Acting ◽  
Underlying Mechanisms ◽  
Palindromic Sequences ◽  
Genetic Rearrangements

A palindrome in DNA consists of two closely spaced or adjacent inverted repeats. Certain palindromes have important biological functions as parts of various cis-acting elements and protein binding sites. However, many palindromes are known as fragile sites in the genome, sites prone to chromosome breakage which can lead to various genetic rearrangements or even cell death. The ability of certain palindromes to initiate genetic recombination lies in their ability to form secondary structures in DNA which can cause replication stalling and double-strand breaks. Given their recombinogenic nature, it is not surprising that palindromes in the human genome are involved in genetic rearrangements in cancer cells as well as other known recurrent translocations and deletions associated with certain syndromes in humans. Here, we bring an overview of current understanding and knowledge on molecular mechanisms of palindrome recombinogenicity and discuss possible implications of DNA palindromes in carcinogenesis. Furthermore, we overview the data on known palindromic sequences in the human genome and efforts to estimate their number and distribution, as well as underlying mechanisms of genetic rearrangements specific palindromic sequences cause.

scholarly journals Rad52 oligomeric N-terminal domain stabilizes Rad51 nucleoprotein filaments and contributes to their protection against Srs2

2021 ◽  
Author(s):  
Emilie Ma ◽  
Laurent Maloisel ◽  
Lea Le Falher ◽  
Raphael Guerois ◽  
Eric Coic
Keyword(s):  
Genome Stability ◽  
Ring Structure ◽  
Homologous Sequence ◽  
Filament Formation ◽  
Repair Synthesis ◽  
Terminal Domain ◽  
Mediator Protein ◽  
Dna Repair Synthesis

Homologous recombination (HR) depends on the formation of a nucleoprotein filament of the recombinase Rad51 to scan the genome and invade the homologous sequence used as template for DNA repair synthesis. Therefore, HR is highly accurate and crucial for genome stability. Rad51 filament formation is controlled by positive and negative factors. In Saccharomyces cerevisiae, the mediator protein Rad52 catalyzes Rad51 filament formation and stabilizes them, mostly by counteracting the disruptive activity of the translocase Srs2. Srs2 activity is essential to avoid the formation of toxic Rad51 filaments, as revealed by Srs2-deficient cells. We previously reported that Rad52 SUMOylation or mutations disrupting the Rad52-Rad51 interaction suppress Rad51 filament toxicity because they disengage Rad52 from Rad51 filaments and reduce their stability. Here, we found that mutations in Rad52 N-terminal domain also suppress the DNA damage sensitivity of Srs2-deficient cells without disturbing Rad52 mediator and pairing activity, both in vivo and in vitro. Structural studies showed that these mutations affect the Rad52 oligomeric ring structure. Overall, our findings indicate that Rad52 ring structure is important for protecting Rad51 filaments from Srs2, but can increase Rad51 filament stability and toxicity in Srs2-deficient cells. This stabilization function is distinct from Rad52 mediator and annealing activities.

scholarly journals Molecular Mechanism of Global Genome Nucleotide Excision Repair

Acta Naturae ◽  
2014 ◽  
Vol 6 (1) ◽  
pp. 23-34 ◽  
Author(s):  
I. O. Petruseva ◽  
A. N. Evdokimov ◽  
O. I. Lavrik
Keyword(s):  
Nucleotide Excision Repair ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Excision Repair ◽  
Current Knowledge ◽  
Wide Spectrum ◽  
Double Helix ◽  
Repair Synthesis ◽  
Nucleotide Excision ◽  
Dna Repair Synthesis

Nucleotide excision repair (NER) is a multistep process that recognizes and eliminates a wide spectrum of damage causing significant distortions in the DNA structure, such as UV-induced damage and bulky chemical adducts. The consequences of defective NER are apparent in the clinical symptoms of individuals affected by three disorders associated with reduced NER capacities: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). These disorders have in common increased sensitivity to UV irradiation, greatly elevated cancer incidence (XP), and multi-system immunological and neurological disorders. The eucaryotic NER system eliminates DNA damage by the excision of 24-32 nt single-strand oligonucleotides from a damaged strand, followed by restoration of an intact double helix by DNA repair synthesis and DNA ligation. About 30 core polypeptides are involved in the entire repair process. NER consists of two pathways distinct in initial damage sensor proteins: transcription-coupled repair (TC-NER) and global genome repair (GG-NER). The article reviews current knowledge on the molecular mechanisms underlying damage recognition and its elimination from mammalian DNA.

scholarly journals ATRX Promotes DNA Repair Synthesis and Sister Chromatid Exchange during Homologous Recombination

2018 ◽  
Vol 71 (1) ◽  
pp. 11-24.e7 ◽  
Author(s):  
Szilvia Juhász ◽  
Amira Elbakry ◽  
Arthur Mathes ◽  
Markus Löbrich
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Sister Chromatid ◽  
Sister Chromatid Exchange ◽  
Repair Synthesis ◽  
Dna Repair Synthesis

scholarly journals Replication Stress Response Links RAD52 to Protecting Common Fragile Sites

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1467 ◽  
Author(s):  
Xiaohua Wu
Keyword(s):  
Mammalian Cells ◽  
Genome Stability ◽  
Replication Stress ◽  
Fragile Sites ◽  
Replication Forks ◽  
Cancer Genes ◽  
Repair Synthesis ◽  
Common Fragile Sites ◽  
Dna Repair Synthesis ◽  
Therapy Target

Rad52 in yeast is a key player in homologous recombination (HR), but mammalian RAD52 is dispensable for HR as shown by the lack of a strong HR phenotype in RAD52-deficient cells and in RAD52 knockout mice. RAD52 function in mammalian cells first emerged with the discovery of its important backup role to BRCA (breast cancer genes) in HR. Recent new evidence further demonstrates that RAD52 possesses multiple activities to cope with replication stress. For example, replication stress-induced DNA repair synthesis in mitosis (MiDAS) and oncogene overexpression-induced DNA replication are dependent on RAD52. RAD52 becomes essential in HR to repair DSBs containing secondary structures, which often arise at collapsed replication forks. RAD52 is also implicated in break-induced replication (BIR) and is found to inhibit excessive fork reversal at stalled replication forks. These various functions of RAD52 to deal with replication stress have been linked to the protection of genome stability at common fragile sites, which are often associated with the DNA breakpoints in cancer. Therefore, RAD52 has important recombination roles under special stress conditions in mammalian cells, and presents as a promising anti-cancer therapy target.

scholarly journals Pathways for maintenance of telomeres and common fragile sites during DNA replication stress

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 180018 ◽  
Author(s):  
Özgün Özer ◽  
Ian D. Hickson
Keyword(s):  
Dna Replication ◽  
Molecular Mechanisms ◽  
Replication Stress ◽  
Fragile Sites ◽  
Repair Synthesis ◽  
Common Fragile Sites ◽  
The Face ◽  
Dna Replication Stress ◽  
Dna Repair Synthesis ◽  
Insight Into

Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.

scholarly journals Rad52 Oligomeric N-Terminal Domain Stabilizes Rad51 Nucleoprotein Filaments and Contributes to Their Protection against Srs2

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1467
Author(s):  
Emilie Ma ◽  
Laurent Maloisel ◽  
Léa Le Falher ◽  
Raphaël Guérois ◽  
Eric Coïc
Keyword(s):  
Genome Stability ◽  
Ring Structure ◽  
Homologous Sequence ◽  
Filament Formation ◽  
Repair Synthesis ◽  
Terminal Domain ◽  
Mediator Protein ◽  
Dna Repair Synthesis

Homologous recombination (HR) depends on the formation of a nucleoprotein filament of the recombinase Rad51 to scan the genome and invade the homologous sequence used as a template for DNA repair synthesis. Therefore, HR is highly accurate and crucial for genome stability. Rad51 filament formation is controlled by positive and negative factors. In Saccharomyces cerevisiae, the mediator protein Rad52 catalyzes Rad51 filament formation and stabilizes them, mostly by counteracting the disruptive activity of the translocase Srs2. Srs2 activity is essential to avoid the formation of toxic Rad51 filaments, as revealed by Srs2-deficient cells. We previously reported that Rad52 SUMOylation or mutations disrupting the Rad52–Rad51 interaction suppress Rad51 filament toxicity because they disengage Rad52 from Rad51 filaments and reduce their stability. Here, we found that mutations in Rad52 N-terminal domain also suppress the DNA damage sensitivity of Srs2-deficient cells. Structural studies showed that these mutations affect the Rad52 oligomeric ring structure. Overall, in vivo and in vitro analyzes of these mutants indicate that Rad52 ring structure is important for protecting Rad51 filaments from Srs2, but can increase Rad51 filament stability and toxicity in Srs2-deficient cells. This stabilization function is distinct from Rad52 mediator and annealing activities.

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