scholarly journals Transcription-Replication Collisions—A Series of Unfortunate Events

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1249
Author(s):  
Commodore St Germain ◽  
Hongchang Zhao ◽  
Jacqueline H. Barlow
Keyword(s):  
Mammalian Cells ◽  
Replication Fork ◽  
Dna Supercoiling ◽  
Genome Integrity ◽  
High Fidelity ◽  
Chromatin Binding ◽  
Cellular Pathways ◽  
Genomic Regions ◽  
Dna Template ◽  
Transcription And Replication

Transcription-replication interactions occur when DNA replication encounters genomic regions undergoing transcription. Both replication and transcription are essential for life and use the same DNA template making conflicts unavoidable. R-loops, DNA supercoiling, DNA secondary structure, and chromatin-binding proteins are all potential obstacles for processive replication or transcription and pose an even more potent threat to genome integrity when these processes co-occur. It is critical to maintaining high fidelity and processivity of transcription and replication while navigating through a complex chromatin environment, highlighting the importance of defining cellular pathways regulating transcription-replication interaction formation, evasion, and resolution. Here we discuss how transcription influences replication fork stability, and the safeguards that have evolved to navigate transcription-replication interactions and maintain genome integrity in mammalian cells.

scholarly journals The role of chromatin at transcription-replication conflicts as a genome safeguard

2021 ◽  
Author(s):  
Aleix Bayona-Feliu ◽  
Andrés Aguilera
Keyword(s):  
Cellular Response ◽  
Replication Fork ◽  
Genome Instability ◽  
Current Knowledge ◽  
Genome Integrity ◽  
Physiological Relevance ◽  
A Genome ◽  
Dna Template ◽  
Transcription And Replication

DNA replication ensures the correct copying of the genome and the faithful transfer of the genetic information to the offspring. However, obstacles to replication fork (RF) progression cause RF stalling and compromise efficient genome duplication. Since replication uses the same DNA template as transcription, both transcription and replication must be coordinated to prevent Transcription-Replication Conflicts (TRCs) that could stall RF progression. Several factors contribute to limit the occurrence of such conflicts and their harmful impact on genome integrity. Increasing evidence indicates that chromatin homeostasis plays a key role in the cellular response to TRCs as well as in the preservation of genome integrity. Indeed, chromatin regulating enzymes are frequently mutated in cancer cells, a common characteristic of which is genome instability. Therefore, understanding the role of chromatin in TRC occurrence and resolution may help identify the molecular mechanism by which chromatin protects genome integrity, and the causes and physiological relevance of the high mutation rates of chromatin regulating factors in cancer. Here we review the current knowledge in the field, as well as the perspectives and future applications.

scholarly journals DNA2 drives processing and restart of reversed replication forks in human cells

2015 ◽  
Vol 208 (5) ◽  
pp. 545-562 ◽  
Author(s):  
Saravanabhavan Thangavel ◽  
Matteo Berti ◽  
Maryna Levikova ◽  
Cosimo Pinto ◽  
Shivasankari Gomathinayagam ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Genotoxic Stress ◽  
Genome Integrity ◽  
High Fidelity ◽  
Replication Forks ◽  
Genomic Integrity ◽  
Replication Restart ◽  
Replication Intermediates ◽  
Dependent Mechanism

Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5′-to-3′ polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors.

scholarly journals MRNIP is a replication fork protection factor

2020 ◽  
Vol 6 (28) ◽  
pp. eaba5974 ◽  
Author(s):  
L. G. Bennett ◽  
A. M. Wilkie ◽  
E. Antonopoulou ◽  
I. Ceppi ◽  
A. Sanchez ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Replication Fork ◽  
Chromosome Instability ◽  
Genome Integrity ◽  
Replication Forks ◽  
Protection Factor ◽  
Replication Fork Progression ◽  
Dna Junctions ◽  
Genomic Regions ◽  
Stalled Replication Forks

The remodeling of stalled replication forks to form four-way DNA junctions is an important component of the replication stress response. Nascent DNA at the regressed arms of these reversed forks is protected by RAD51 and the tumor suppressors BRCA1/2, and when this function is compromised, stalled forks undergo pathological MRE11-dependent degradation, leading to chromosomal instability. However, the mechanisms regulating MRE11 functions at reversed forks are currently unclear. Here, we identify the MRE11-binding protein MRNIP as a novel fork protection factor that directly binds to MRE11 and specifically represses its exonuclease activity. The loss of MRNIP results in impaired replication fork progression, MRE11 exonuclease–dependent degradation of reversed forks, persistence of underreplicated genomic regions, chemosensitivity, and chromosome instability. Our findings identify MRNIP as a novel regulator of MRE11 at reversed forks and provide evidence that regulation of specific MRE11 nuclease activities ensures protection of nascent DNA and thereby genome integrity.

Early signalling events of autophagy

2013 ◽  
Vol 55 ◽  
pp. 1-15 ◽  
Author(s):  
Laura E. Gallagher ◽  
Edmond Y.W. Chan
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Mammalian Cells ◽  
Mammalian Target Of Rapamycin ◽  
Interacting Protein ◽  
The Core ◽  
Autophagy Gene ◽  
Autophagy Induction ◽  
Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

scholarly journals A Tale of Ice and Fire: The Dual Role for 17β-Estradiol in Balancing DNA Damage and Genome Integrity

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1583
Author(s):  
Sara Pescatori ◽  
Francesco Berardinelli ◽  
Jacopo Albanesi ◽  
Paolo Ascenzi ◽  
Maria Marino ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Transformation ◽  
Genome Integrity ◽  
Physiological Effects ◽  
Dna Damages ◽  
Cellular Effects ◽  
Damage Response ◽  
17Β Estradiol ◽  
Cellular Pathways ◽  
Definition Of

17β-estradiol (E2) regulates human physiology both in females and in males. At the same time, E2 acts as a genotoxic substance as it could induce DNA damages, causing the initiation of cellular transformation. Indeed, increased E2 plasma levels are a risk factor for the development of several types of cancers including breast cancer. This paradoxical identity of E2 undermines the foundations of the physiological definition of “hormone” as E2 works both as a homeostatic regulator of body functions and as a genotoxic compound. Here, (i) the molecular circuitries underlying this double face of E2 are reviewed, and (ii) a possible framework to reconcile the intrinsic discrepancies of the E2 function is reported. Indeed, E2 is a regulator of the DNA damage response, which this hormone exploits to calibrate its genotoxicity with its physiological effects. Accordingly, the genes required to maintain genome integrity belong to the E2-controlled cellular signaling network and are essential for the appearance of the E2-induced cellular effects. This concept requires an “upgrade” to the vision of E2 as a “genotoxic hormone”, which balances physiological and detrimental pathways to guarantee human body homeostasis. Deregulation of this equilibrium between cellular pathways would determine the E2 pathological effects.

Human RecQ helicases in transcription-associated stress management: bridging the gap between DNA and RNA metabolism

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Tulika Das ◽  
Surasree Pal ◽  
Agneyo Ganguly
Keyword(s):  
Genome Integrity ◽  
Complex Structures ◽  
Huge Number ◽  
Dna Helicases ◽  
Dna Structures ◽  
Recq Helicases ◽  
Dna And Rna ◽  
Cellular Dna ◽  
Almost All ◽  
Transcription And Replication

Abstract RecQ helicases are a highly conserved class of DNA helicases that play crucial role in almost all DNA metabolic processes including replication, repair and recombination. They are able to unwind a wide variety of complex intermediate DNA structures that may result from cellular DNA transactions and hence assist in maintaining genome integrity. Interestingly, a huge number of recent reports suggest that many of the RecQ family helicases are directly or indirectly involved in regulating transcription and gene expression. On one hand, they can remove complex structures like R-loops, G-quadruplexes or RNA:DNA hybrids formed at the intersection of transcription and replication. On the other hand, emerging evidence suggests that they can also regulate transcription by directly interacting with RNA polymerase or recruiting other protein factors that may regulate transcription. This review summarizes the up to date knowledge on the involvement of three human RecQ family proteins BLM, WRN and RECQL5 in transcription regulation and management of transcription associated stress.

scholarly journals Dissection of acute stimulus-inducible nucleosome remodeling in mammalian cells

2019 ◽  
Author(s):  
Federico Comoglio ◽  
Marta Simonatto ◽  
Sara Polletti ◽  
Xin Liu ◽  
Stephen T. Smale ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Regulatory Elements ◽  
Micrococcal Nuclease ◽  
Nucleosome Remodeling ◽  
Nucleosome Dynamics ◽  
Nucleosome Organization ◽  
Regulatory Information ◽  
Different Types ◽  
Genomic Regions ◽  
The Impact

ABSTRACTAccessibility of the genomic regulatory information is largely controlled by the nucleosome-organizing activity of transcription factors (TFs). Whereas stimulus-induced TFs bind to genomic regions that are maintained accessible by lineage-determining TFs, they also increase accessibility of thousands of cis-regulatory elements. Nucleosome remodeling events underlying such changes and their interplay with basal positioning are unknown. Here, we devised a novel quantitative framework discriminating different types of nucleosome remodeling events in micrococcal nuclease ChIP-seq datasets and used it to analyze nucleosome dynamics at stimulus-regulated cis-regulatory elements. At enhancers, remodeling preferentially affected poorly positioned nucleosomes while sparing well-positioned nucleosomes flanking the enhancer core, indicating that inducible TFs do not suffice to overrule basal nucleosomal organization maintained by lineage-determining TFs. Remodeling events appeared to be combinatorially driven by multiple TFs, with distinct TFs showing however different remodeling efficiencies. Overall, these data provide a systematic view of the impact of stimulation on nucleosome organization and genome accessibility in mammalian cells.

Pyrimidine dimers block simian virus 40 replication forks

1986 ◽  
Vol 6 (10) ◽  
pp. 3443-3450
Author(s):  
C A Berger ◽  
H J Edenberg
Keyword(s):  
Mammalian Cells ◽  
Replication Fork ◽  
Uv Light ◽  
Large Fraction ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
Replication Forks ◽  
Pyrimidine Dimers ◽  
Leading Strand ◽  
Uv Lesions

UV light produces lesions, predominantly pyrimidine dimers, which inhibit DNA replication in mammalian cells. The mechanism of inhibition is controversial: is synthesis of a daughter strand halted at a lesion while the replication fork moves on and reinitiates downstream, or is fork progression itself blocked for some time at the site of a lesion? We directly addressed this question by using electron microscopy to examine the distances of replication forks from the origin in unirradiated and UV-irradiated simian virus 40 chromosomes. If UV lesions block replication fork progression, the forks should be asymmetrically located in a large fraction of the irradiated molecules; if replication forks move rapidly past lesions, the forks should be symmetrically located. A large fraction of the simian virus 40 replication forks in irradiated molecules were asymmetrically located, demonstrating that UV lesions present at the frequency of pyrimidine dimers block replication forks. As a mechanism for this fork blockage, we propose that polymerization of the leading strand makes a significant contribution to the energetics of fork movement, so any lesion in the template for the leading strand which blocks polymerization should also block fork movement.

scholarly journals Basal CHK1 activity safeguards its stability to maintain intrinsic S-phase checkpoint functions

2019 ◽  
Vol 218 (9) ◽  
pp. 2865-2875 ◽  
Author(s):  
Jone Michelena ◽  
Marco Gatti ◽  
Federico Teloni ◽  
Ralph Imhof ◽  
Matthias Altmeyer
Keyword(s):  
Cell Proliferation ◽  
Steady State ◽  
Cell Survival ◽  
Replication Fork ◽  
S Phase ◽  
Genome Integrity ◽  
Replication Machinery ◽  
Replication Fork Progression ◽  
Steady State Activity ◽  
S Phase Checkpoint

The DNA replication machinery frequently encounters impediments that slow replication fork progression and threaten timely and error-free replication. The CHK1 protein kinase is essential to deal with replication stress (RS) and ensure genome integrity and cell survival, yet how basal levels and activity of CHK1 are maintained under physiological, unstressed conditions is not well understood. Here, we reveal that CHK1 stability is controlled by its steady-state activity during unchallenged cell proliferation. This autoactivatory mechanism, which depends on ATR and its coactivator ETAA1 and is tightly associated with CHK1 autophosphorylation at S296, counters CHK1 ubiquitylation and proteasomal degradation, thereby preventing attenuation of S-phase checkpoint functions and a compromised capacity to respond to RS. Based on these findings, we propose that steady-state CHK1 activity safeguards its stability to maintain intrinsic checkpoint functions and ensure genome integrity and cell survival.

scholarly journals Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
André Franz ◽  
Paul A. Pirson ◽  
Domenic Pilger ◽  
Swagata Halder ◽  
Divya Achuthankutty ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dynamic Process ◽  
Metabolic Pathways ◽  
Replication Fork ◽  
Genome Instability ◽  
Genome Integrity ◽  
Substrate Selection ◽  
Replication Fork Progression ◽  
Replication Factors ◽  
Spatiotemporal Control

Abstract The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemporal control of distinct CDC-48/p97 substrates in the chromatin environment remained unclear. Here, we report that progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes. Consequently, inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics accompanied by pronounced replication stress and eventually resulting in genome instability. Our work identifies a critical substrate selection module of CDC-48/p97 required for chromatin-associated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.

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