scholarly journals Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1960
Author(s):  
Julian Spies ◽  
Hana Polasek-Sedlackova ◽  
Jiri Lukas ◽  
Kumar Somyajit
Keyword(s):  
Dna Replication ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Genetic Material ◽  
Therapeutic Interventions ◽  
Genome Replication ◽  
Cancer Evolution ◽  
Intrinsic Factors ◽  
Surveillance Mechanism ◽  
Dna Template

Accurate and complete genome replication is a fundamental cellular process for the proper transfer of genetic material to cell progenies, normal cell growth, and genome stability. However, a plethora of extrinsic and intrinsic factors challenge individual DNA replication forks and cause replication stress (RS), a hallmark of cancer. When challenged by RS, cells deploy an extensive range of mechanisms to safeguard replicating genomes and limit the burden of DNA damage. Prominent among those is homologous recombination (HR). Although fundamental to cell division, evidence suggests that cancer cells exploit and manipulate these RS responses to fuel their evolution and gain resistance to therapeutic interventions. In this review, we focused on recent insights into HR-mediated protection of stress-induced DNA replication intermediates, particularly the repair and protection of daughter strand gaps (DSGs) that arise from discontinuous replication across a damaged DNA template. Besides mechanistic underpinnings of this process, which markedly differ depending on the extent and duration of RS, we highlight the pathophysiological scenarios where DSG repair is naturally silenced. Finally, we discuss how such pathophysiological events fuel rampant mutagenesis, promoting cancer evolution, but also manifest in adaptative responses that can be targeted for cancer therapy.

scholarly journals The impact of transcription-mediated replication stress on genome instability and human disease

2020 ◽  
Vol 1 (5) ◽  
pp. 207-234
Author(s):  
Stefano Gnan ◽  
Yaqun Liu ◽  
Manuela Spagnuolo ◽  
Chun-Long Chen
Keyword(s):  
Dna Replication ◽  
Gene Transcription ◽  
Human Disease ◽  
Genome Stability ◽  
Genome Instability ◽  
Current Knowledge ◽  
Replication Stress ◽  
Genome Replication ◽  
Living Organisms ◽  
The Impact

Abstract DNA replication is a vital process in all living organisms. At each cell division, > 30,000 replication origins are activated in a coordinated manner to ensure the duplication of > 6 billion base pairs of the human genome. During differentiation and development, this program must adapt to changes in chromatin organization and gene transcription: its deregulation can challenge genome stability, which is a leading cause of many diseases including cancers and neurological disorders. Over the past decade, great progress has been made to better understand the mechanisms of DNA replication regulation and how its deregulation challenges genome integrity and leads to human disease. Growing evidence shows that gene transcription has an essential role in shaping the landscape of genome replication, while it is also a major source of endogenous replication stress inducing genome instability. In this review, we discuss the current knowledge on the various mechanisms by which gene transcription can impact on DNA replication, leading to genome instability and human disease.

scholarly journals Bacterial DNA repair genes and their eukaryotic homologues: 5. The role of recombination in DNA repair and genome stability.

2007 ◽  
Vol 54 (3) ◽  
pp. 483-494 ◽  
Author(s):  
Anetta Nowosielska
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Replication ◽  
Homologous Recombination ◽  
Genetic Material ◽  
Double Strand Breaks ◽  
Single Strand ◽  
Biological Processes ◽  
Strand Breaks ◽  
Immune System Development

Recombinational repair is a well conserved DNA repair mechanism present in all living organisms. Repair by homologous recombination is generally accurate as it uses undamaged homologous DNA molecule as a repair template. In Escherichia coli homologous recombination repairs both the double-strand breaks and single-strand gaps in DNA. DNA double-strand breaks (DSB) can be induced upon exposure to exogenous sources such as ionizing radiation or endogenous DNA-damaging agents including reactive oxygen species (ROS) as well as during natural biological processes like conjugation. However, the bulk of double strand breaks are formed during replication fork collapse encountering an unrepaired single strand gap in DNA. Under such circumstances DNA replication on the damaged template can be resumed only if supported by homologous recombination. This functional cooperation of homologous recombination with replication machinery enables successful completion of genome duplication and faithful transmission of genetic material to a daughter cell. In eukaryotes, homologous recombination is also involved in essential biological processes such as preservation of genome integrity, DNA damage checkpoint activation, DNA damage repair, DNA replication, mating type switching, transposition, immune system development and meiosis. When unregulated, recombination can lead to genome instability and carcinogenesis.

Homologous recombination in Archaea: new Holliday junction helicases

2003 ◽  
Vol 31 (3) ◽  
pp. 703-705 ◽  
Author(s):  
E.L. Bolt ◽  
C.P. Guy
Keyword(s):  
Dna Replication ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Holliday Junction ◽  
High Fidelity ◽  
Dna Helicases ◽  
Branched Dna ◽  
Archaeal Species ◽  
Domains Of Life ◽  
Methanothermobacter Thermautotrophicus

Homologous recombination (HR) maintains genome stability by promoting high fidelity DNA repair. Several recent reports have established that the primary function of HR enzymes is to underpin DNA replication, resetting forks that are blocked or collapsed at sites of DNA damage remote from replication origins. These functions are crucial to ensuring that genomes are transmitted successfully into subsequent generations of cells. Enzymes of HR have been unearthed in all three domains of life: bacteria, Archaea and eukarya. Helicases that specifically unwind branched DNA molecules are pivotal in linking HR and DNA replication in bacteria. However, knowledge of helicases with these functions in eukaryotes is vague and is wholly absent in Archaea. We are using the archaeal species Methanothermobacter thermautotrophicus to identify new DNA helicases of homologous recombination.

scholarly journals Conditional knockout of RAD51-related genes in Leishmania major reveals a critical role for homologous recombination during genome replication

2019 ◽  
Author(s):  
Jeziel D. Damasceno ◽  
João Reis-Cunha ◽  
Kathryn Crouch ◽  
Craig Lapsley ◽  
Luiz R. O. Tosi ◽  
...  
Keyword(s):  
Dna Replication ◽  
Homologous Recombination ◽  
Dna Synthesis ◽  
Leishmania Major ◽  
Critical Role ◽  
Dna Lesions ◽  
Replication Initiation ◽  
Conditional Knockout ◽  
Genome Replication ◽  
Genome Wide

AbstractHomologous recombination (HR) has an intimate relationship with genome replication, both during repair of DNA lesions that might prevent DNA synthesis and in tackling stalls to the replication fork. Recent studies led us to ask if HR might have a more central role in replicating the genome of Leishmania, a eukaryotic parasite. Conflicting evidence has emerged regarding whether or not HR genes are essential, and genome-wide mapping has provided evidence for an unorthodox organisation of DNA replication initiation sites, termed origins. To answer this question, we have employed a combined CRISPR/Cas9 and DiCre approach to rapidly generate and assess the effect of conditional ablation of RAD51 and three RAD51-related proteins in Leishmania major. Using this approach, we demonstrate that loss of any of these HR factors is not immediately lethal, but in each case growth slows with time and leads to DNA damage, accumulation of cells with aberrant DNA content, and genome-wide mutation. Despite these similarities, we show that only loss of RAD51 and RAD51-3 impairs DNA synthesis, and that the factors act in distinct ways. Finally, we reveal that loss of RAD51 has a profound effect on DNA replication, causing loss of initiation at the major origins and increased DNA synthesis at subtelomeres. Our work clarifies questions regarding the importance of HR to survival of Leishmania and reveals an unanticipated, central role for RAD51 in the programme of genome replication in a microbial eukaryote.

scholarly journals Termination of DNA replication at Tus-ter barriers results in under-replication of template DNA

2021 ◽  
Author(s):  
Katie H. Jameson ◽  
Christian J. Rudolph ◽  
Michelle Hawkins
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Genome Stability ◽  
Processing Enzymes ◽  
Replication Fork Progression ◽  
Evolutionary Advantage ◽  
Domains Of Life ◽  
Dna Template ◽  
Template Dna

ABSTRACTThe complete and accurate duplication of genomic information is vital to maintain genome stability in all domains of life. In Escherichia coli, replication termination, the final stage of the duplication process, is confined to the ‘replication fork trap’ region by multiple unidirectional fork barriers formed by the binding of Tus protein to genomic ter sites. Termination typically occurs away from Tus-ter complexes, but they become part of the fork fusion process when a delay to one replisome allows the second to travel more than halfway around the chromosome. In this instance, replisome progression is blocked at the non-permissive interface of Tus-ter and termination occurs when a converging replisome meets the non-permissive interface. To investigate the consequences of replication fork fusion at Tus-ter complexes, we established a plasmid-based replication system where we could mimic the termination process at Tus-ter in vitro. We developed a termination mapping assay to measure leading strand replication fork progression and demonstrate that the DNA template is under-replicated by 15-24 bases when replication forks fuse at Tus-ter complexes. This gap could not be closed by the inclusion of lagging strand processing enzymes as well as several helicases that promote DNA replication. Our results indicate that accurate fork fusion at Tus-ter barriers requires further enzymatic processing, highlighting large gaps that still exist in our understanding of the final stages of chromosome duplication and the evolutionary advantage of having a replication fork trap.

DNA replication and homologous recombination factors: acting together to maintain genome stability

Chromosoma ◽  
2013 ◽  
Vol 122 (5) ◽  
pp. 401-413 ◽  
Author(s):  
Antoine Aze ◽  
Jin Chuan Zhou ◽  
Alessandro Costa ◽  
Vincenzo Costanzo
Keyword(s):  
Dna Replication ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Maintain Genome Stability

scholarly journals The Regulation of Homologous Recombination by Helicases

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 498 ◽  
Author(s):  
Eric Huselid ◽  
Samuel F. Bunting
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Genetic Material ◽  
Tumor Formation ◽  
Dna Breaks ◽  
Successful Completion ◽  
Subsequent Formation ◽  
Increased Risk ◽  
Dna Template ◽  
Dna Ends

Homologous recombination is essential for DNA repair, replication and the exchange of genetic material between parental chromosomes during meiosis. The stages of recombination involve complex reorganization of DNA structures, and the successful completion of these steps is dependent on the activities of multiple helicase enzymes. Helicases of many different families coordinate the processing of broken DNA ends, and the subsequent formation and disassembly of the recombination intermediates that are necessary for template-based DNA repair. Loss of recombination-associated helicase activities can therefore lead to genomic instability, cell death and increased risk of tumor formation. The efficiency of recombination is also influenced by the ‘anti-recombinase’ effect of certain helicases, which can direct DNA breaks toward repair by other pathways. Other helicases regulate the crossover versus non-crossover outcomes of repair. The use of recombination is increased when replication forks and the transcription machinery collide, or encounter lesions in the DNA template. Successful completion of recombination in these situations is also regulated by helicases, allowing normal cell growth, and the maintenance of genomic integrity.

RecA family proteins in archaea: RadA and its cousins

2009 ◽  
Vol 37 (1) ◽  
pp. 102-107 ◽  
Author(s):  
Sam Haldenby ◽  
Malcolm F. White ◽  
Thorsten Allers
Keyword(s):  
Phylogenetic Analysis ◽  
Dna Replication ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Model Organisms ◽  
Replication Forks ◽  
Dna Breaks ◽  
Double Stranded Dna

Recombinases of the RecA family are essential for homologous recombination and underpin genome stability, by promoting the repair of double-stranded DNA breaks and the rescue of collapsed DNA replication forks. Until now, our understanding of homologous recombination has relied on studies of bacterial and eukaryotic model organisms. Archaea provide new opportunities to study how recombination operates in a lineage distinct from bacteria and eukaryotes. In the present paper, we focus on RadA, the archaeal RecA family recombinase, and its homologues in archaea and other domains. On the basis of phylogenetic analysis, we propose that a family of archaeal proteins with a single RecA domain, which are currently annotated as KaiC, be renamed aRadC.

PrimPol (Primase/Polymerase), replicating enzyme – A mini review

2020 ◽  
Vol 2 (4) ◽  
pp. 89-92
Author(s):  
Muhammad Amir ◽  
Sabeera Afzal ◽  
Alia Ishaq
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Genetic Information ◽  
Nuclear Dna ◽  
De Novo ◽  
Dna Polymerases ◽  
Test Site ◽  
Mitochondrial Dna Replication ◽  
Dna Template ◽  
Preliminary Phase

Polymerases were revealed first in 1970s. Most important to the modest perception the enzyme responsible for nuclear DNA replication that was pol , for DNA repair pol and for mitochondrial DNA replication pol  DNA construction and renovation done by DNA polymerases, so directing both the constancy and discrepancy of genetic information. Replication of genome initiate with DNA template-dependent fusion of small primers of RNA. This preliminary phase in replication of DNA demarcated as de novo primer synthesis which is catalyzed by specified polymerases known as primases. Sixteen diverse DNA-synthesizing enzymes about human perspective are devoted to replication, reparation, mutilation lenience, and inconsistency of nuclear DNA. But in dissimilarity, merely one DNA polymerase has been called in mitochondria. It has been suggest that PrimPol is extremely acting the roles by re-priming DNA replication in mitochondria to permit an effective and appropriate way replication to be accomplished. Investigations from a numeral of test site have significantly amplified our appreciative of the role, recruitment and regulation of the enzyme during DNA replication. Though, we are simply just start to increase in value the versatile roles that play PrimPol in eukaryote.

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