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Current Opinion in Genetics &... Dec 2021Break-induced replication (BIR) is a pathway specialized in repair of double-strand DNA breaks with only one end capable of invading homologous template that can arise... (Review)
Review
Break-induced replication (BIR) is a pathway specialized in repair of double-strand DNA breaks with only one end capable of invading homologous template that can arise following replication collapse, telomere erosion or DNA cutting by site-specific endonucleases. For a long time, yeast remained the only model system to study BIR. Studies in yeast demonstrated that BIR represents an unusual mode of DNA synthesis that is driven by a migrating bubble and leads to conservative inheritance of newly synthesized DNA. This unusual type of DNA synthesis leads to high levels of mutations and chromosome rearrangements. Recently, multiple examples of BIR were uncovered in mammalian cells that allowed the comparison of BIR between organisms. It appeared initially that BIR in mammalian cells is predominantly independent of RAD51, and therefore different from BIR that is predominantly Rad51-dependent in yeast. However, a series of systematic studies utilizing site-specific DNA breaks for BIR initiation in mammalian reporters led to the discovery of highly efficient RAD51-dependent BIR, allowing side-by side comparison with BIR in yeast which is the focus of this review.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Mammals; Saccharomyces cerevisiae
PubMed: 34481360
DOI: 10.1016/j.gde.2021.08.002 -
PLoS Genetics Dec 2022Replication fork reversal which restrains DNA replication progression is an important protective mechanism in response to replication stress. PARP1 is recruited to...
Replication fork reversal which restrains DNA replication progression is an important protective mechanism in response to replication stress. PARP1 is recruited to stalled forks to restrain DNA replication. However, PARP1 has no helicase activity, and the mechanism through which PARP1 participates in DNA replication restraint remains unclear. Here, we found novel protein-protein interactions between PARP1 and DNA translocases, including HLTF, SHPRH, ZRANB3, and SMARCAL1, with HLTF showing the strongest interaction among these DNA translocases. Although HLTF and SHPRH share structural and functional similarity, it remains unclear whether SHPRH contains DNA translocase activity. We further identified the ability of SHPRH to restrain DNA replication upon replication stress, indicating that SHPRH itself could be a DNA translocase or a helper to facilitate DNA translocation. Although hydroxyurea (HU) and MMS induce different types of replication stress, they both induce common DNA replication restraint mechanisms independent of intra-S phase activation. Our results suggest that the PARP1 facilitates DNA translocase recruitment to damaged forks, preventing fork collapse and facilitating DNA repair.
Topics: DNA-Binding Proteins; Transcription Factors; DNA Repair; DNA Replication; DNA; DNA Damage
PubMed: 36512630
DOI: 10.1371/journal.pgen.1010545 -
PLoS Genetics Oct 2016As the ratio of the copy number of the most replicated to the unreplicated regions in the same chromosome, the definition of chromosomal replication complexity (CRC)... (Review)
Review
As the ratio of the copy number of the most replicated to the unreplicated regions in the same chromosome, the definition of chromosomal replication complexity (CRC) appears to leave little room for variation, being either two during S-phase or one otherwise. However, bacteria dividing faster than they replicate their chromosome spike CRC to four and even eight. A recent experimental inquiry about the limits of CRC in Escherichia coli revealed two major reasons to avoid elevating it further: (i) increased chromosomal fragmentation and (ii) complications with subsequent double-strand break repair. Remarkably, examples of stable elevated CRC in eukaryotic chromosomes are well known under various terms like "differential replication," "underreplication," "DNA puffs," "onion-skin replication," or "re-replication" and highlight the phenomenon of static replication fork (sRF). To accurately describe the resulting "amplification by overinitiation," I propose a new term: "replification" (subchromosomal overreplication). In both prokaryotes and eukaryotes, replification, via sRF processing, causes double-strand DNA breaks and, with their repair elevating chromosomal rearrangements, represents a novel genome instability factor. I suggest how static replication bubbles could be stabilized and speculate that some tandem duplications represent such persistent static bubbles. Moreover, I propose how static replication bubbles could be transformed into tandem duplications, double minutes, or inverted triplications. Possible experimental tests of these models are discussed.
Topics: Chromosomes, Bacterial; DNA Breaks, Double-Stranded; DNA Repair; DNA Replication; Escherichia coli; Genomic Instability; Models, Genetic
PubMed: 27711112
DOI: 10.1371/journal.pgen.1006229 -
Advances in Experimental Medicine and... 2017Eukaryotic genomes are replicated starting from multiple origins of replication. Their usage is tightly regulated, and not all the potential origins are activated during... (Review)
Review
Eukaryotic genomes are replicated starting from multiple origins of replication. Their usage is tightly regulated, and not all the potential origins are activated during a single cell cycle. In addition, the ones that are activated are activated in a sequential order. Why don't origins of replication normally all fire together? Is this important? And if so, why? Would any order of firing do, or does the specific sequence matter? How is this process regulated? These questions concern all eukaryotes but have proven extremely hard to address because replication timing is a process intricately connected with multiple aspects of nuclear function.
Topics: Animals; Cell Cycle Proteins; Cell Division; DNA Replication; DNA Replication Timing; Genome; Genomic Instability; Humans; Mammals; Telomere-Binding Proteins
PubMed: 29357062
DOI: 10.1007/978-981-10-6955-0_12 -
Cell Cycle (Georgetown, Tex.) Jan 2017
Topics: Animals; Chromatids; Chromosomes; DNA Replication; Humans; Models, Biological; Oncogenes; RNA, Long Noncoding
PubMed: 27736302
DOI: 10.1080/15384101.2016.1241604 -
Cell Reports Apr 2022Mitotic DNA synthesis (MiDAS) has been proposed to restart DNA synthesis during mitosis because of replication fork stalling in late interphase caused by mild...
Mitotic DNA synthesis (MiDAS) has been proposed to restart DNA synthesis during mitosis because of replication fork stalling in late interphase caused by mild replication stress (RS). Contrary to this proposal, we find that cells exposed to mild RS in fact maintain continued DNA replication throughout G2 and during G2-M transition in RAD51- and RAD52-dependent manners. Persistent DNA synthesis is necessary to resolve replication intermediates accumulated in G2 and disengage an ATR-imposed block to mitotic entry. Because of its continual nature, DNA synthesis at very late replication sites can overlap with chromosome condensation, generating the phenomenon of mitotic DNA synthesis. Unexpectedly, we find that the commonly used CDK1 inhibitor RO3306 interferes with replication to preclude detection of G2 DNA synthesis, leading to the impression of a mitosis-driven response. Our study reveals the importance of persistent DNA replication and checkpoint control to lessen the risk for severe genome under-replication under mild RS.
Topics: DNA; DNA Replication; Mitosis
PubMed: 35443178
DOI: 10.1016/j.celrep.2022.110701 -
Nature Communications Aug 2018Discriminating the contribution of unmodifiable random intrinsic DNA replication errors ('bad luck') to cancer development from those of other factors is critical for... (Review)
Review
Discriminating the contribution of unmodifiable random intrinsic DNA replication errors ('bad luck') to cancer development from those of other factors is critical for understanding cancer in humans and for directing public resources aimed at reducing the burden of cancer. Here, we review and highlight the evidence that demonstrates cancer causation is multifactorial, and provide several important examples where modification of risk factors has achieved cancer prevention. Furthermore, we stress the need and opportunities to advance understanding of cancer aetiology through integration of interaction effects between risk factors when estimating the contribution of individual and joint factors to cancer burden in a population. We posit that non-intrinsic factors drive most cancer risk, and stress the need for cancer prevention.
Topics: Animals; DNA Replication; Humans; Neoplasms; Risk Factors
PubMed: 30154431
DOI: 10.1038/s41467-018-05467-z -
Journal of Molecular Biology Jan 2024TIMELESS protein (TIM) protects replication forks from stalling at difficult-to-replicate regions and plays an important role in DNA damage response, including... (Review)
Review
TIMELESS protein (TIM) protects replication forks from stalling at difficult-to-replicate regions and plays an important role in DNA damage response, including checkpoint signaling, protection of stalled replication forks and DNA repair. Loss of TIM causes severe replication stress, while its overexpression is common in various types of cancer, providing protection from DNA damage and resistance to chemotherapy. Although TIM has mostly been studied for its part in replication stress response, its additional roles in supporting genome stability and a wide variety of other cellular pathways are gradually coming to light. This review discusses the diverse functions of TIM and its orthologs in healthy and cancer cells, open questions, and potential future directions.
Topics: Humans; Carrier Proteins; Cell Cycle Proteins; DNA Damage; DNA Replication; DNA-Binding Proteins; Genomic Instability; Intracellular Signaling Peptides and Proteins; Nuclear Proteins
PubMed: 37481157
DOI: 10.1016/j.jmb.2023.168206 -
Cellular and Molecular Life Sciences :... Nov 2021During duplication of the genome, eukaryotic cells may experience various exogenous and endogenous replication stresses that impede progression of DNA replication along... (Review)
Review
During duplication of the genome, eukaryotic cells may experience various exogenous and endogenous replication stresses that impede progression of DNA replication along chromosomes. Chemical alterations in template DNA, imbalances of deoxynucleotide pools, repetitive sequences, tight DNA-protein complexes, and conflict with transcription can negatively affect the replication machineries. If not properly resolved, stalled replication forks can cause chromosome breaks leading to genomic instability and tumor development. Replication stress is enhanced in cancer cells due, for example, to the loss of DNA repair genes or replication-transcription conflict caused by activation of oncogenic pathways. To prevent these serious consequences, cells are equipped with diverse mechanisms that enhance the resilience of replication machineries to replication stresses. This review describes DNA damage responses activated at stressed replication forks and summarizes current knowledge on the pathways that promote faithful chromosome replication and protect chromosome integrity, including ATR-dependent replication checkpoint signaling, DNA cross-link repair, and SLX4-mediated responses to tight DNA-protein complexes that act as barriers. This review also focuses on the relevance of replication stress responses to selective cancer chemotherapies.
Topics: Animals; Chromosomes; DNA; DNA Damage; DNA Repair; DNA Replication; Humans; Proteins
PubMed: 34463774
DOI: 10.1007/s00018-021-03926-3 -
The EMBO Journal Nov 2018The DNA replication checkpoint (DRC) and the DNA damage checkpoint (DDC) are two closely linked signaling cascades that adjust S phase to the presence of DNA lesions and... (Review)
Review
The DNA replication checkpoint (DRC) and the DNA damage checkpoint (DDC) are two closely linked signaling cascades that adjust S phase to the presence of DNA lesions and other replication impediments. Two recent studies published in shed new light on their relationship in budding yeast, collectively showing that the two pathways—while sharing several factors—differ in the location and kinetics of their activation, suggesting that they constitute different branches of an integrated cellular response to impaired DNA replication.
Topics: DNA Damage; DNA Replication; DNA, Fungal; S Phase; Saccharomyces cerevisiae
PubMed: 30287420
DOI: 10.15252/embj.2018100681