scholarly journals p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sunetra Roy ◽  
Karl-Heinz Tomaszowski ◽  
Jessica W Luzwick ◽  
Soyoung Park ◽  
Jun Li ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
Genome Instability ◽  
Single Cells ◽  
Replication Forks ◽  
Mutational Signatures ◽  
Development Of Resistance ◽  
Cycle Arrest ◽  
Replication Restart ◽  
Dna Replication Restart

Classically, p53 tumor suppressor acts in transcription, apoptosis, and cell cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks that drive genomic instability, which isgenetically separable from transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53-mediated suppression of replication genome instability.

scholarly journals p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis

2017 ◽  
Author(s):  
Sunetra Roy ◽  
Karl-Heinz Tomaszowski ◽  
Jessica Luzwick ◽  
Soyoung Park ◽  
Jun Li ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
Genome Instability ◽  
Single Cells ◽  
Replication Forks ◽  
Mutational Signatures ◽  
Development Of Resistance ◽  
Cycle Arrest ◽  
Replication Restart ◽  
Dna Replication Restart

ABSTRACTClassically, p53 tumor-suppressor acts in transcription, apoptosis, and cell-cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks driving genomic instability independent of transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53 suppression of replication genome instability.

Helicases that interact with replication forks: new candidates from archaea

2005 ◽  
Vol 33 (6) ◽  
pp. 1471-1473 ◽  
Author(s):  
E.L. Bolt
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Replication Fork ◽  
Genome Duplication ◽  
Genome Instability ◽  
Replication Forks ◽  
Valuable Resource ◽  
Replication Restart

Overcoming DNA replication fork blocks is essential for completing genome duplication and cell division. Archaea and eukaryotes drive replication using essentially the same protein machinery. Archaea may be a valuable resource for identifying new helicase components at advancing forks and/or in replication-restart pathways. As described here, these may be relevant to understanding genome instability in metazoans.

scholarly journals Examination of the roles of a conserved motif in the PriA helicase in structure-specific DNA unwinding and processivity

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255409
Author(s):  
Alexander T. Duckworth ◽  
Tricia A. Windgassen ◽  
James L. Keck
Keyword(s):  
Dna Replication ◽  
Dna Helicase ◽  
Sequence Motif ◽  
Dna Unwinding ◽  
Helicase Domain ◽  
Replication Forks ◽  
Dna Helicases ◽  
Conserved Sequence ◽  
Replication Restart ◽  
Dna Replication Restart

DNA replication complexes (replisomes) frequently encounter barriers that can eject them prematurely from the genome. To avoid the lethality of incomplete DNA replication that arises from these events, bacteria have evolved “DNA replication restart” mechanisms to reload replisomes onto abandoned replication forks. The Escherichia coli PriA DNA helicase orchestrates this process by recognizing and remodeling replication forks and recruiting additional proteins that help to drive replisome reloading. We have identified a conserved sequence motif within a linker region of PriA that docks into a groove on the exterior of the PriA helicase domain. Alterations to the motif reduce the apparent processivity and attenuate structure-specific helicase activity in PriA, implicating the motif as a potential autoregulatory element in replication fork processing. The study also suggests that multiple PriA molecules may function in tandem to enhance DNA unwinding processivity, highlighting an unexpected similarity between PriA and other DNA helicases.

scholarly journals DNA Helicase-SSB Interactions Critical to the Regression and Restart of Stalled DNA Replication Forks in Escherichia coli

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 471 ◽  
Author(s):  
Piero R. Bianco
Keyword(s):  
Escherichia Coli ◽  
Dna Replication ◽  
Dna Helicase ◽  
Dependent Manner ◽  
Replication Forks ◽  
Replication Restart ◽  
Helicase Dnab ◽  
Fork Regression ◽  
Ob Fold ◽  
Dna Replication Restart

In Escherichia coli, DNA replication forks stall on average once per cell cycle. When this occurs, replisome components disengage from the DNA, exposing an intact, or nearly intact fork. Consequently, the fork structure must be regressed away from the initial impediment so that repair can occur. Regression is catalyzed by the powerful, monomeric DNA helicase, RecG. During this reaction, the enzyme couples unwinding of fork arms to rewinding of duplex DNA resulting in the formation of a Holliday junction. RecG works against large opposing forces enabling it to clear the fork of bound proteins. Following subsequent processing of the extruded junction, the PriA helicase mediates reloading of the replicative helicase DnaB leading to the resumption of DNA replication. The single-strand binding protein (SSB) plays a key role in mediating PriA and RecG functions at forks. It binds to each enzyme via linker/OB-fold interactions and controls helicase-fork loading sites in a substrate-dependent manner that involves helicase remodeling. Finally, it is displaced by RecG during fork regression. The intimate and dynamic SSB-helicase interactions play key roles in ensuring fork regression and DNA replication restart.

Single-molecule binding characterization of primosomal protein PriA involved in replication restart

2021 ◽  
Author(s):  
Tzu-Yu Lee ◽  
Yi-Ching Li ◽  
Min-Guan Lin ◽  
Chwan-Deng Hsiao ◽  
Hung-Wen Li
Keyword(s):  
Dna Replication ◽  
Dna Synthesis ◽  
Single Molecule ◽  
Replication Forks ◽  
Bacterial Survival ◽  
Dna Damages ◽  
Replication Restart

DNA damages lead to stalled or collapsed replication forks. Replication restart primosomes re-initiate DNA synthesis at these stalled or collapsed DNA replication forks, which is important for bacterial survival. Primosomal...

scholarly journals EXO1 resection at G-quadruplex structures facilitates resolution and replication

2020 ◽  
Vol 48 (9) ◽  
pp. 4960-4975 ◽  
Author(s):  
Susanna Stroik ◽  
Kevin Kurtz ◽  
Kevin Lin ◽  
Sergey Karachenets ◽  
Chad L Myers ◽  
...  
Keyword(s):  
Dna Replication ◽  
Genomic Instability ◽  
Secondary Structures ◽  
Replication Forks ◽  
End Joining ◽  
G Quadruplex ◽  
Exonuclease 1 ◽  
Telomere Loss

Abstract G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.

scholarly journals Mechanisms of bacterial DNA replication restart

2017 ◽  
Vol 46 (2) ◽  
pp. 504-519 ◽  
Author(s):  
Tricia A Windgassen ◽  
Sarah R Wessel ◽  
Basudeb Bhattacharyya ◽  
James L Keck
Keyword(s):  
Dna Replication ◽  
Bacterial Dna ◽  
Replication Restart ◽  
Dna Replication Restart ◽  
Bacterial Dna Replication
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