scholarly journals Mind the replication gap

2021 ◽  
Vol 8 (6) ◽  
pp. 201932
Author(s):  
Camelia Mocanu ◽  
Kok-Lung Chan
Keyword(s):  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Fragile Site ◽  
Chromosome Instability ◽  
Repair Synthesis ◽  
Dna Structures ◽  
Delay Cell ◽  
Dna Repair Synthesis ◽  
Genomic Regions ◽  
Break Induced Replication

Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.

Soluble and insoluble nickel compounds induce DNA repair synthesis in cultured mammalian cells☆

1983 ◽  
Vol 17 (3) ◽  
pp. 273-279 ◽  
Author(s):  
Steven H. Robison ◽  
Orazio Cantoni ◽  
J.Daniel Heck ◽  
Max Costa
Keyword(s):  
Dna Repair ◽  
Mammalian Cells ◽  
Repair Synthesis ◽  
Nickel Compounds ◽  
Dna Repair Synthesis

Effect of split doses of N-methyl-N-nitrosourea on DNA repair synthesis in cultured mammalian cells

1977 ◽  
Vol 3 ◽  
pp. 183-188 ◽  
Author(s):  
Luciano Zardi ◽  
Leone St. Vincent ◽  
Alain Barbin ◽  
Ruggero Montesano ◽  
Geoffrey P. Margison
Keyword(s):  
Dna Repair ◽  
Mammalian Cells ◽  
Repair Synthesis ◽  
Dna Repair Synthesis

scholarly journals Long‐patch DNA repair synthesis during base excision repair in mammalian cells

EMBO Reports ◽  
2003 ◽  
Vol 4 (4) ◽  
pp. 363-367 ◽  
Author(s):  
Ulrike Sattler ◽  
Philippe Frit ◽  
Bernard Salles ◽  
Patrick Calsou
Keyword(s):  
Dna Repair ◽  
Base Excision Repair ◽  
Mammalian Cells ◽  
Excision Repair ◽  
Repair Synthesis ◽  
Base Excision ◽  
Dna Repair Synthesis

scholarly journals Overproduction of the poly(ADP-ribose) polymerase DNA-binding domain blocks alkylation-induced DNA repair synthesis in mammalian cells.

1993 ◽  
Vol 12 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
M. Molinete ◽  
W. Vermeulen ◽  
A. Bürkle ◽  
J. Ménissier-de Murcia ◽  
J.H. Küpper ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dna Binding ◽  
Mammalian Cells ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Repair Synthesis ◽  
Dna Repair Synthesis

scholarly journals Modeling Chromosome Maintenance as a Property of Cell Cycle in Saccharomyces cerevisiae

2016 ◽  
Author(s):  
Jesse P. Frumkin ◽  
Biranchi N. Patra ◽  
Antony Sevold ◽  
Kumkum Ganguly ◽  
Chaya Patel ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Numerical Technique ◽  
Chromosome Instability ◽  
Molecular Genetic ◽  
Linear Optimization ◽  
Optimal Arrangement ◽  
Yeast Saccharomyces Cerevisiae ◽  
Repair Synthesis ◽  
Dna Repair Synthesis

Defects in DNA repair, synthesis, and chromosome transmission can often cause chromosome instability, which are understood with respect to molecular-genetic mechanisms. However, transition from descriptive models to quantitative ones is generally difficult. Here we use a computationally intensive numerical technique based on linear programming to analyze the processes of chromosome maintenance during the cell cycle in yeast, Saccharomyces cerevisiae. We first experimentally identify 19 genes that when ectopically expressed cause chromosome instability. We then build an 18 x 19 matrix by assaying the genetic interactions of pairs of genes that each normally functions to maintain chromosomes, including the 19 genes discovered here. We then use a 'seriation' algorithm based on linear optimization to find an optimal arrangement of rows and columns to confirm an optimum temporal arrangement of gene influence during cell cycle phases. We experimentally demonstrate that the method yields new biological insights, which we test and validate.

scholarly journals Molecular Basis for Expression of Common and Rare Fragile Sites

2003 ◽  
Vol 23 (20) ◽  
pp. 7143-7151 ◽  
Author(s):  
Eitan Zlotorynski ◽  
Ayelet Rahat ◽  
Jennifer Skaug ◽  
Neta Ben-Porat ◽  
Efrat Ozeri ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Fragile Site ◽  
Secondary Structures ◽  
Fragile Sites ◽  
Entire Genome ◽  
Common Fragile Sites ◽  
Dna Structures ◽  
Significant Difference ◽  
Minisatellite Repeats ◽  
Genomic Regions

ABSTRACT Fragile sites are specific loci that form gaps, constrictions, and breaks on chromosomes exposed to partial replication stress and are rearranged in tumors. Fragile sites are classified as rare or common, depending on their induction and frequency within the population. The molecular basis of rare fragile sites is associated with expanded repeats capable of adopting unusual non-B DNA structures that can perturb DNA replication. The molecular basis of common fragile sites was unknown. Fragile sites from R-bands are enriched in flexible sequences relative to nonfragile regions from the same chromosomal bands. Here we cloned FRA7E, a common fragile site mapped to a G-band, and revealed a significant difference between its flexibility and that of nonfragile regions mapped to G-bands, similar to the pattern found in R-bands. Thus, in the entire genome, flexible sequences might play a role in the mechanism of fragility. The flexible sequences are composed of interrupted runs of AT-dinucleotides, which have the potential to form secondary structures and hence can affect replication. These sequences show similarity to the AT-rich minisatellite repeats that underlie the fragility of the rare fragile sites FRA16B and FRA10B. We further demonstrate that the normal alleles of FRA16B and FRA10B span the same genomic regions as the common fragile sites FRA16C and FRA10E. Our results suggest that a shared molecular basis, conferred by sequences with a potential to form secondary structures that can perturb replication, may underlie the fragility of rare fragile sites harboring AT-rich minisatellite repeats and aphidicolin-induced common fragile sites.

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 Polθ reverse transcribes RNA and promotes RNA-templated DNA repair

2021 ◽  
Vol 7 (24) ◽  
pp. eabf1771
Author(s):  
Gurushankar Chandramouly ◽  
Jiemin Zhao ◽  
Shane McDevitt ◽  
Timur Rusanov ◽  
Trung Hoang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Dna Repair ◽  
Mammalian Cells ◽  
Dna Polymerases ◽  
Hydroxyl Groups ◽  
Dna Breaks ◽  
Repair Synthesis ◽  
Reverse Transcriptases ◽  
Dna Repair Synthesis ◽  
Multiple Hydrogen Bonds

Genome-embedded ribonucleotides arrest replicative DNA polymerases (Pols) and cause DNA breaks. Whether mammalian DNA repair Pols efficiently use template ribonucleotides and promote RNA-templated DNA repair synthesis remains unknown. We find that human Polθ reverse transcribes RNA, similar to retroviral reverse transcriptases (RTs). Polθ exhibits a significantly higher velocity and fidelity of deoxyribonucleotide incorporation on RNA versus DNA. The 3.2-Å crystal structure of Polθ on a DNA/RNA primer-template with bound deoxyribonucleotide reveals that the enzyme undergoes a major structural transformation within the thumb subdomain to accommodate A-form DNA/RNA and forms multiple hydrogen bonds with template ribose 2′-hydroxyl groups like retroviral RTs. Last, we find that Polθ promotes RNA-templated DNA repair in mammalian cells. These findings suggest that Polθ was selected to accommodate template ribonucleotides during DNA repair.

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