scholarly journals The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks

2009 ◽  
Vol 23 (20) ◽  
pp. 2405-2414 ◽  
Author(s):  
C. E. Bansbach ◽  
R. Betous ◽  
C. A. Lovejoy ◽  
G. G. Glick ◽  
D. Cortez
Keyword(s):  
Genome Integrity ◽  
Replication Forks ◽  
Stalled Replication Forks

Chemical strategies for development of ATR inhibitors

2014 ◽  
Vol 16 ◽  
Author(s):  
Sabin Llona-Minguez ◽  
Andreas Höglund ◽  
Sylvain A. Jacques ◽  
Tobias Koolmeister ◽  
Thomas Helleday
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Checkpoint Inhibitors ◽  
Genome Integrity ◽  
Signalling Pathways ◽  
Replication Forks ◽  
Damage Response ◽  
Key Players ◽  
Chemical Strategies ◽  
Stalled Replication Forks

ATR protein kinase is one of the key players in maintaining genome integrity and coordinating of the DNA damage response and repair signalling pathways. Inhibition of ATR prevents signalling from stalled replication forks and enhances the formation of DNA damage, particularly under conditions of replication stress present in cancers. For this reason ATR/CHK1 checkpoint inhibitors can potentiate the effect of DNA cross-linking agents, as evidenced by ATR inhibitors recently entering human clinical trials. This review aims to compile the existing literature on small molecule inhibitors of ATR, both from academia and the pharmaceutical industry, and will provide the reader with a comprehensive summary of this promising oncology target.

scholarly journals ETAA1 acts at stalled replication forks to maintain genome integrity

2016 ◽  
Vol 18 (11) ◽  
pp. 1185-1195 ◽  
Author(s):  
Thomas E. Bass ◽  
Jessica W. Luzwick ◽  
Gina Kavanaugh ◽  
Clinton Carroll ◽  
Huzefa Dungrawala ◽  
...  
Keyword(s):  
Genome Integrity ◽  
Replication Forks ◽  
Stalled Replication Forks

scholarly journals RAD51 and mitotic function of mus81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

2019 ◽  
Vol 47 (13) ◽  
pp. 6796-6810 ◽  
Author(s):  
Francesca Antonella Aiello ◽  
Anita Palma ◽  
Eva Malacaria ◽  
Li Zheng ◽  
Judith L Campbell ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Genome Instability ◽  
Genome Integrity ◽  
Replication Forks ◽  
Wild Type ◽  
Alternative Processing ◽  
Mitotic Abnormalities ◽  
Mitotic Phosphorylation ◽  
Stalled Replication Forks

Abstract Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death.

scholarly journals WRNIP1: A new guardian of genome integrity at stalled replication forks

2016 ◽  
Vol 3 (5) ◽  
pp. e1215777
Author(s):  
Giuseppe Leuzzi ◽  
Veronica Marabitti ◽  
Pietro Pichierri ◽  
Annapaola Franchitto
Keyword(s):  
Genome Integrity ◽  
Replication Forks ◽  
Stalled Replication Forks

scholarly journals Human CST complex protects replication fork stability by directly blocking MRE11 degradation of nascent strand DNA

2019 ◽  
Author(s):  
Xinxing Lyu ◽  
Kai-Hang Lei ◽  
Olga Shiva ◽  
Megan Chastain ◽  
Peter Chi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Replication Fork ◽  
Genome Instability ◽  
Genome Integrity ◽  
Replication Forks ◽  
Cellular Sensitivity ◽  
Fork Stalling ◽  
Stalled Replication Forks ◽  
Nuclease Degradation

AbstractDegradation and collapse of stalled replication forks are main sources of genome instability, yet the molecular mechanism for protecting forks from degradation/collapse is not well understood. Here, we report that human CST (CTC1-STN1-TEN1), a single-stranded DNA binding protein complex, localizes at stalled forks and protects forks from MRE11 nuclease degradation upon replication perturbation. CST deficiency causes nascent strand degradation, ssDNA accumulation after fork stalling, and delay in replication recovery, leading to cellular sensitivity to fork stalling agents. Purified CST binds to 5’ overhangs and directly blocks MRE11 degradation in vitro, and the DNA binding ability of CST is required for blocking MRE11-mediated nascent strand degradation. Finally, we uncover that CST and BRCA2 form non-overlapping foci upon fork stalling, and CST inactivation is synthetic with BRCA2 deficiency in inducing genome instability. Collectively, our findings identify CST as an important fork protector to preserve genome integrity under replication perturbation.

scholarly journals Advances in understanding DNA processing and protection at stalled replication forks

2019 ◽  
Vol 218 (4) ◽  
pp. 1096-1107 ◽  
Author(s):  
Kimberly Rickman ◽  
Agata Smogorzewska
Keyword(s):  
Mammalian Cells ◽  
Replication Stress ◽  
Genome Integrity ◽  
Replication Forks ◽  
Damage Response ◽  
Dna Translocases ◽  
Brca1 Brca2 ◽  
Stalled Replication Forks ◽  
Insight Into

The replisome, the molecular machine dedicated to copying DNA, encounters a variety of obstacles during S phase. Without a proper response to this replication stress, the genome becomes unstable, leading to disease, including cancer. The immediate response is localized to the stalled replisome and includes protection of the nascent DNA. A number of recent studies have provided insight into the factors recruited to and responsible for protecting stalled replication forks. In response to replication stress, the SNF2 family of DNA translocases has emerged as being responsible for remodeling replication forks in vivo. The protection of stalled replication forks requires the cooperation of RAD51, BRCA1, BRCA2, and many other DNA damage response proteins. In the absence of these fork protection factors, fork remodeling renders them vulnerable to degradation by nucleases and helicases, ultimately compromising genome integrity. In this review, we focus on the recent progress in understanding the protection, processing, and remodeling of stalled replication forks in mammalian cells.

scholarly journals Destabilization of the holo-DNA Polδ by loss of Pol32 confers conditional lethality that can be suppressed by stabilizing Pol31-Pol3 interaction

2021 ◽  
Author(s):  
Kenji Shimada ◽  
Monika Tsai-Pflugfelder ◽  
Niloofar Davoodi Vijeh Motlagh ◽  
Neda Delgoshaie ◽  
Jeannette Fuchs ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Replication Fork ◽  
Essential Role ◽  
Genome Integrity ◽  
Genome Replication ◽  
Replication Forks ◽  
Kinase Activation ◽  
Yeast Strains ◽  
Stalled Replication Forks ◽  
Conserved Amino Acids

AbstractDNA Polymerase δ plays an essential role in genome replication and in the preservation of genome integrity. In S. cerevisiae, Polδ consists of three subunits: Pol3 (the catalytic subunit), Pol31 and Pol32. We have constructed pol31 mutants by alanine substitution at conserved amino acids, and identified three alleles that do not confer any disadvantage on their own, but which suppress the cold-, HU- and MMS-hypersensitivity of yeast strains lacking Pol32. We have shown that Pol31 and Pol32 are both involved in translesion synthesis, error-free bypass synthesis, and in preservation of replication fork stability under conditions of HU arrest. We identified a solvent exposed loop in Pol31 defined by two alanine substitutions at T415 and W417. Whereas pol31-T4l5A compromises polymerase stability at stalled forks, pol31-W417A is able to suppress many, but not all, of the phenotypes arising from pol32Δ. ChIP analyses showed that the absence of Pol32 destabilizes Pole and Polα at stalled replication forks, but does not interfere with checkpoint kinase activation. We show that the Pol31-W417A-mediated suppression of replicationstress sensitivity in pol32Δ stems from enhanced interaction between Pol3 and Pol31, which stabilizes a functional Polδ.

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.

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