scholarly journals Inhibition of DNA replication fork progression and mutagenic potential of 1, N6-ethenoadenine and 8-oxoguanine in human cell extracts

2007 ◽  
Vol 36 (4) ◽  
pp. 1300-1308 ◽  
Author(s):  
J. H. Tolentino ◽  
T. J. Burke ◽  
S. Mukhopadhyay ◽  
W. G. McGregor ◽  
A. K. Basu
Keyword(s):  
Dna Replication ◽  
Human Cell ◽  
Replication Fork ◽  
Mutagenic Potential ◽  
Replication Fork Progression ◽  
Cell Extracts

scholarly journals A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression

2014 ◽  
Vol 42 (9) ◽  
pp. 5605-5615 ◽  
Author(s):  
Spencer W. Luebben ◽  
Tsuyoshi Kawabata ◽  
Charles S. Johnson ◽  
M. Gerard O'Sullivan ◽  
Naoko Shima
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Genome Instability ◽  
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 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.

scholarly journals Mms1 and Mms22 stabilize the replisome during replication stress

2011 ◽  
Vol 22 (13) ◽  
pp. 2396-2408 ◽  
Author(s):  
Jessica A. Vaisica ◽  
Anastasija Baryshnikova ◽  
Michael Costanzo ◽  
Charles Boone ◽  
Grant W. Brown
Keyword(s):  
Dna Replication ◽  
Ubiquitin Ligase ◽  
Replication Fork ◽  
E3 Ubiquitin Ligase ◽  
Replication Stress ◽  
Replication Forks ◽  
Replication Fork Progression ◽  
Binding Partners ◽  
Efficient Recovery ◽  
Stalled Replication Forks

Mms1 and Mms22 form a Cul4Ddb1-like E3 ubiquitin ligase with the cullin Rtt101. In this complex, Rtt101 is bound to the substrate-specific adaptor Mms22 through a linker protein, Mms1. Although the Rtt101Mms1/Mms22ubiquitin ligase is important in promoting replication through damaged templates, how it does so has yet to be determined. Here we show that mms1Δ and mms22Δ cells fail to properly regulate DNA replication fork progression when replication stress is present and are defective in recovery from replication fork stress. Consistent with a role in promoting DNA replication, we find that Mms1 is enriched at sites where replication forks have stalled and that this localization requires the known binding partners of Mms1—Rtt101 and Mms22. Mms1 and Mms22 stabilize the replisome during replication stress, as binding of the fork-pausing complex components Mrc1 and Csm3, and DNA polymerase ε, at stalled replication forks is decreased in mms1Δ and mms22Δ. Taken together, these data indicate that Mms1 and Mms22 are important for maintaining the integrity of the replisome when DNA replication forks are slowed by hydroxyurea and thereby promote efficient recovery from replication stress.

scholarly journals The Human Tim/Tipin Complex Coordinates an Intra-S Checkpoint Response to UV That Slows Replication Fork Displacement

2007 ◽  
Vol 27 (8) ◽  
pp. 3131-3142 ◽  
Author(s):  
Keziban Ünsal-Kaçmaz ◽  
Paul D. Chastain ◽  
Ping-Ping Qu ◽  
Parviz Minoo ◽  
Marila Cordeiro-Stone ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Protein A ◽  
Chain Elongation ◽  
Replication Forks ◽  
Interacting Protein ◽  
Checkpoint Response ◽  
Replication Fork Progression ◽  
Dna Chain ◽  
Interfering Rna

ABSTRACT UV-induced DNA damage stalls DNA replication forks and activates the intra-S checkpoint to inhibit replicon initiation. In response to stalled replication forks, ATR phosphorylates and activates the transducer kinase Chk1 through interactions with the mediator proteins TopBP1, Claspin, and Timeless (Tim). Murine Tim recently was shown to form a complex with Tim-interacting protein (Tipin), and a similar complex was shown to exist in human cells. Knockdown of Tipin using small interfering RNA reduced the expression of Tim and reversed the intra-S checkpoint response to UVC. Tipin interacted with replication protein A (RPA) and RPA-coated DNA, and RPA promoted the loading of Tipin onto RPA-free DNA. Immunofluorescence analysis of spread DNA fibers showed that treating HeLa cells with 2.5 J/m2 UVC not only inhibited the initiation of new replicons but also reduced the rate of chain elongation at active replication forks. The depletion of Tim and Tipin reversed the UV-induced inhibition of replicon initiation but affected the rate of DNA synthesis at replication forks in different ways. In undamaged cells depleted of Tim, the apparent rate of replication fork progression was 52% of the control. In contrast, Tipin depletion had little or no effect on fork progression in unirradiated cells but significantly attenuated the UV-induced inhibition of DNA chain elongation. Together, these findings indicate that the Tim-Tipin complex mediates the UV-induced intra-S checkpoint, Tim is needed to maintain DNA replication fork movement in the absence of damage, Tipin interacts with RPA on DNA and, in UV-damaged cells, Tipin slows DNA chain elongation in active replicons.

scholarly journals RMI1 Promotes DNA Replication Fork Progression and Recovery from Replication Fork Stress

2012 ◽  
Vol 32 (15) ◽  
pp. 3054-3064 ◽  
Author(s):  
J. Yang ◽  
L. O'Donnell ◽  
D. Durocher ◽  
G. W. Brown
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Replication Fork Progression

scholarly journals Histone deacetylases 1 and 2 maintain S-phase chromatin and DNA replication fork progression

2013 ◽  
Vol 6 (1) ◽  
Author(s):  
Srividya Bhaskara ◽  
Vincent Jacques ◽  
James R Rusche ◽  
Eric N Olson ◽  
Bradley R Cairns ◽  
...  
Keyword(s):  
Dna Replication ◽  
Histone Deacetylases ◽  
Replication Fork ◽  
S Phase ◽  
Replication Fork Progression
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