scholarly journals Rif1 inhibits replication fork progression and controls DNA copy number in Drosophila

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Alexander Munden ◽  
Zhan Rong ◽  
Amanda Sun ◽  
Rama Gangula ◽  
Simon Mallal ◽  
...  
Keyword(s):  
Copy Number ◽  
Replication Fork ◽  
Genome Stability ◽  
Replication Timing ◽  
Dependent Manner ◽  
Replication Forks ◽  
Dna Copy Number ◽  
Replication Fork Progression ◽  
Suur Protein ◽  
Maintain Genome Stability

Control of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR’s SNF2 domain, we identified an interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in a partially SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.

scholarly journals Rif1 inhibits replication fork progression and controls DNA copy number in Drosophila

2018 ◽  
Author(s):  
Alexander Munden ◽  
Zhan Rong ◽  
Rama Gangula ◽  
Simon Mallal ◽  
Jared T. Nordman
Keyword(s):  
Copy Number ◽  
Replication Fork ◽  
Genome Stability ◽  
Replication Timing ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Replication Forks ◽  
Dna Copy Number ◽  
Replication Fork Progression ◽  
Maintain Genome Stability

ABSTRACTControl of DNA copy number is essential to maintain genome stability and ensure proper cell and tissue function. In Drosophila polyploid cells, the SNF2-domain-containing SUUR protein inhibits replication fork progression within specific regions of the genome to promote DNA underreplication. While dissecting the function of SUUR’s SNF2 domain, we identified a physical interaction between SUUR and Rif1. Rif1 has many roles in DNA metabolism and regulates the replication timing program. We demonstrate that repression of DNA replication is dependent on Rif1. Rif1 localizes to active replication forks in an SUUR-dependent manner and directly regulates replication fork progression. Importantly, SUUR associates with replication forks in the absence of Rif1, indicating that Rif1 acts downstream of SUUR to inhibit fork progression. Our findings uncover an unrecognized function of the Rif1 protein as a regulator of replication fork progression.

scholarly journals Replication timing analysis in polyploid cells reveals Rif1 uses multiple mechanisms to promote underreplication in Drosophila

Genetics ◽  
2021 ◽  
Author(s):  
Souradip Das ◽  
Madison Caballero ◽  
Tatyana Kolesnikova ◽  
Igor Zhimulev ◽  
Amnon Koren ◽  
...  
Keyword(s):  
Dna Replication ◽  
Copy Number ◽  
Genome Stability ◽  
Timing Analysis ◽  
Replication Timing ◽  
Critical Function ◽  
Replication Fork Progression ◽  
Polyploid Cells ◽  
Genomic Regions ◽  
Insight Into

Abstract Regulation of DNA replication and copy number is necessary to promote genome stability and maintain cell and tissue function. DNA replication is regulated temporally in a process known as replication timing (RT). Rap1-interacting factor 1 (Rif1) is a key regulator of RT and has a critical function in copy number control in polyploid cells. Previously, we demonstrated that Rif1 functions with SUUR to inhibit replication fork progression and promote underreplication (UR) of specific genomic regions. How Rif1-dependent control of RT factors into its ability to promote UR is unknown. By applying a computational approach to measure RT in Drosophila polyploid cells, we show that SUUR and Rif1 have differential roles in controlling UR and RT. Our findings reveal that Rif1 acts to promote late replication, which is necessary for SUUR-dependent underreplication. Our work provides new insight into the process of UR and its links to RT.

scholarly journals Author response: Rif1 inhibits replication fork progression and controls DNA copy number in Drosophila

2018 ◽  
Author(s):  
Alexander Munden ◽  
Zhan Rong ◽  
Amanda Sun ◽  
Rama Gangula ◽  
Simon Mallal ◽  
...  
Keyword(s):  
Copy Number ◽  
Replication Fork ◽  
Author Response ◽  
Dna Copy Number ◽  
Replication Fork Progression

scholarly journals Dual effect of heat shock on DNA replication and genome integrity

2012 ◽  
Vol 23 (17) ◽  
pp. 3450-3460 ◽  
Author(s):  
Artem K. Velichko ◽  
Nadezhda V. Petrova ◽  
Omar L. Kantidze ◽  
Sergey V. Razin
Keyword(s):  
Dna Replication ◽  
Heat Shock ◽  
Replication Fork ◽  
Stress Factors ◽  
Dna Integrity ◽  
Dependent Manner ◽  
Replication Forks ◽  
Replication Process ◽  
Replication Fork Progression ◽  
Dna Damage Signaling

Heat shock (HS) is one of the better-studied exogenous stress factors. However, little is known about its effects on DNA integrity and the DNA replication process. In this study, we show that in G1 and G2 cells, HS induces a countable number of double-stranded breaks (DSBs) in the DNA that are marked by γH2AX. In contrast, in S-phase cells, HS does not induce DSBs but instead causes an arrest or deceleration of the progression of the replication forks in a temperature-dependent manner. This response also provoked phosphorylation of H2AX, which appeared at the sites of replication. Moreover, the phosphorylation of H2AX at or close to the replication fork rescued the fork from total collapse. Collectively our data suggest that in an asynchronous cell culture, HS might affect DNA integrity both directly and via arrest of replication fork progression and that the phosphorylation of H2AX has a protective effect on the arrested replication forks in addition to its known DNA damage signaling function.

scholarly journals Replication timing analysis in polyploid cells reveals Rif1 uses multiple mechanisms to promote underreplication in Drosophila.

2021 ◽  
Author(s):  
Souradip Das ◽  
Madison Caballero ◽  
Tatyana Kolesnikova ◽  
Igor Zhimulev ◽  
Amnon Koren ◽  
...  
Keyword(s):  
Dna Replication ◽  
Copy Number ◽  
Genome Stability ◽  
Timing Analysis ◽  
Replication Timing ◽  
Critical Function ◽  
Replication Fork Progression ◽  
Polyploid Cells ◽  
Genomic Regions ◽  
Insight Into

Regulation of DNA replication and copy number are necessary to promote genome stability and maintain cell and tissue function. DNA replication is regulated temporally in a process known as replication timing (RT). Rif1 is key regulator of RT and has a critical function in copy number control in polyploid cells. In a previous study (Munden et al., 2018), we demonstrated that Rif1 functions with SUUR to inhibit replication fork progression and promote underreplication (UR) of specific genomic regions. How Rif1-dependent control of RT factors into its ability to promote UR is unknown. By applying a computational approach to measure RT in Drosophila polyploid cells, we show that SUUR and Rif1 have differential roles in controlling UR and RT. Our findings reveal that Rif1 functions both upstream and downstream of SUUR to promote UR. Our work provides new mechanistic insight into the process of UR and its links to RT.

scholarly journals Interferon-stimulated gene 15 accelerates replication fork progression inducing chromosomal breakage

2020 ◽  
Vol 219 (8) ◽  
Author(s):  
Maria Chiara Raso ◽  
Nikola Djoric ◽  
Franziska Walser ◽  
Sandra Hess ◽  
Fabian Marc Schmid ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
Genome Stability ◽  
Dna Helicase ◽  
Replication Forks ◽  
Chromosomal Breakage ◽  
Replication Fork Progression ◽  
Ubiquitin System ◽  
Interferon Stimulated Gene 15

DNA replication is highly regulated by the ubiquitin system, which plays key roles upon stress. The ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) is induced by interferons, bacterial and viral infection, and DNA damage, but it is also constitutively expressed in many types of cancer, although its role in tumorigenesis is still largely elusive. Here, we show that ISG15 localizes at the replication forks, in complex with PCNA and the nascent DNA, where it regulates DNA synthesis. Indeed, high levels of ISG15, intrinsic or induced by interferon-β, accelerate DNA replication fork progression, resulting in extensive DNA damage and chromosomal aberrations. This effect is largely independent of ISG15 conjugation and relies on ISG15 functional interaction with the DNA helicase RECQ1, which promotes restart of stalled replication forks. Additionally, elevated ISG15 levels sensitize cells to cancer chemotherapeutic treatments. We propose that ISG15 up-regulation exposes cells to replication stress, impacting genome stability and response to genotoxic drugs.

scholarly journals DNA Copy-Number Control through Inhibition of Replication Fork Progression

Cell Reports ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. 841-849 ◽  
Author(s):  
Jared T. Nordman ◽  
Elena N. Kozhevnikova ◽  
C. Peter Verrijzer ◽  
Alexey V. Pindyurin ◽  
Evgeniya N. Andreyeva ◽  
...  
Keyword(s):  
Copy Number ◽  
Replication Fork ◽  
Dna Copy Number ◽  
Copy Number Control ◽  
Replication Fork Progression

scholarly journals Single-molecule imaging reveals control of parental histone recycling by free histones during DNA replication

2020 ◽  
Vol 6 (38) ◽  
pp. eabc0330 ◽  
Author(s):  
D. T. Gruszka ◽  
S. Xie ◽  
H. Kimura ◽  
H. Yardimci
Keyword(s):  
Dna Replication ◽  
Real Time ◽  
Single Molecule ◽  
Replication Fork ◽  
Epigenetic Inheritance ◽  
Replication Forks ◽  
Replication Fork Progression ◽  
Egg Extracts ◽  
Fork Stalling ◽  
The Moment

During replication, nucleosomes are disrupted ahead of the replication fork, followed by their reassembly on daughter strands from the pool of recycled parental and new histones. However, because no previous studies have managed to capture the moment that replication forks encounter nucleosomes, the mechanism of recycling has remained unclear. Here, through real-time single-molecule visualization of replication fork progression in Xenopus egg extracts, we determine explicitly the outcome of fork collisions with nucleosomes. Most of the parental histones are evicted from the DNA, with histone recycling, nucleosome sliding, and replication fork stalling also occurring but at lower frequencies. Critically, we find that local histone recycling becomes dominant upon depletion of endogenous histones from extracts, revealing that free histone concentration is a key modulator of parental histone dynamics at the replication fork. The mechanistic details revealed by these studies have major implications for our understanding of epigenetic inheritance.

scholarly journals Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandro Cicconi ◽  
Rekha Rai ◽  
Xuexue Xiong ◽  
Cayla Broton ◽  
Amer Al-Hiyasat ◽  
...  
Keyword(s):  
Dna Damage ◽  
Replication Fork ◽  
Clinical Feature ◽  
Replication Forks ◽  
Primary Microcephaly ◽  
Dna Damage And Repair ◽  
Homology Directed Repair ◽  
Replication Fork Progression ◽  
Telomere Binding Protein ◽  
Telomere Replication

AbstractTelomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.

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