Recombination at Collapsed Replication Forks: the Payoff for Survival

Pellicioli, Achille; Foiani, Marco

doi:10.1016/j.molcel.2005.05.018

Cited by 5 publications

(4 citation statements)

References 10 publications

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“…With regard to DNA double strand breaks, we found that only approximately 14% of MCF7 and 9% of NDHF freeze-thawed cells exhibited an enhanced number of γH2AX/53BP1 foci, which is in contrast to numerous studies 42 – 44 , 46 – 48 . Importantly, these cells contained a minimum of 30 γH2AX/53BP1 foci/nucleus, but they typically had more than 100.…”

Section: Discussioncontrasting

confidence: 70%

“…The literature provides differing conclusions regarding cell survival upon extensive replication fork damage 42 – 44 , 46 – 48 ; therefore, it is difficult to predict the fate of freeze-thawed cells affected by this damage, particularly if the cells suffer from additional types of chromatin alterations. For instance, Dixon and colleagues described 56 impaired DNA damage signaling and repair in cells exposed to hyperosmolar microenvironments, which caused chromatin condensation.…”

Section: Discussionmentioning

confidence: 99%

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Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants

Falk

Falková

Kopečná

et al. 2018

Sci Rep

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In this work, we shed new light on the highly debated issue of chromatin fragmentation in cryopreserved cells. Moreover, for the first time, we describe replicating cell-specific DNA damage and higher-order chromatin alterations after freezing and thawing. We identified DNA structural changes associated with the freeze-thaw process and correlated them with the viability of frozen and thawed cells. We simultaneously evaluated DNA defects and the higher-order chromatin structure of frozen and thawed cells with and without cryoprotectant treatment. We found that in replicating (S phase) cells, DNA was preferentially damaged by replication fork collapse, potentially leading to DNA double strand breaks (DSBs), which represent an important source of both genome instability and defects in epigenome maintenance. This induction of DNA defects by the freeze-thaw process was not prevented by any cryoprotectant studied. Both in replicating and non-replicating cells, freezing and thawing altered the chromatin structure in a cryoprotectant-dependent manner. Interestingly, cells with condensed chromatin, which was strongly stimulated by dimethyl sulfoxide (DMSO) prior to freezing had the highest rate of survival after thawing. Our results will facilitate the design of compounds and procedures to decrease injury to cryopreserved cells.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants

Falk

Falková

Kopečná

et al. 2018

Sci Rep

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“…In the absence of checkpoint proteins, such as the Mec1 kinase, stalling replication forks can lead to disengagement of the replisome, resulting in fork collapse along with the formation of DSBs (Lopes et al, 2001;Tercero and Diffley, 2001;Sogo et al, 2002;Pellicioli and Foiani, 2005;Trenz et al, 2006). To determine if the absence of the checkpoint protein Mec1 would trigger an elevated recruitment of HR proteins to DNA replication forks, cells were analyzed for Rad54 foci in the presence or absence of SRS2 in a mec1∆ strain where SML1 was also deleted in order to suppress mec1∆ lethality.…”

Section: Recombination Foci Accumulate In the Absence Of Srs2 Activitymentioning

confidence: 99%

Localization of recombination proteins and Srs2 reveals anti-recombinase function in vivo

Burgess

Lisby

Altmannová

et al. 2009

Journal of Cell Biology

110

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Homologous recombination (HR), although an important DNA repair mechanism, is dangerous to the cell if improperly regulated. The Srs2 “anti-recombinase” restricts HR by disassembling the Rad51 nucleoprotein filament, an intermediate preceding the exchange of homologous DNA strands. Here, we cytologically characterize Srs2 function in vivo and describe a novel mechanism for regulating the initiation of HR. We find that Srs2 is recruited separately to replication and repair centers and identify the genetic requirements for recruitment. In the absence of Srs2 activity, Rad51 foci accumulate, and surprisingly, can form in the absence of Rad52 mediation. However, these Rad51 foci do not represent repair-proficient filaments, as determined by recombination assays. Antagonistic roles for Rad52 and Srs2 in Rad51 filament formation are also observed in vitro. Furthermore, we provide evidence that Srs2 removes Rad51 indiscriminately from DNA, while the Rad52 protein coordinates appropriate filament reformation. This constant breakdown and rebuilding of filaments may act as a stringent quality control mechanism during HR.

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“…The EM result provides an alternative (but not mutually exclusive) model. Many studies of site-specific replication fork barriers have shown that a stalled fork is subject to breakage and elevated recombination (see (62,84) for review).…”

Section: Consequences Of Fork Stalling and Chromosome Breakagementioning

confidence: 99%

Chromosome fragility: molecular mechanisms and cellular consequences

Freudenreich¹

2007

Front Biosci

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Fragile Sites are regions of genomes that are prone to breakage. In human cells, rare fragile sites are due to expansion of repetitive sequences which have been either shown or predicted to form DNA secondary structures such as hairpins, cruciforms, and quadruplexes. For human common fragile sites, which are components of normal chromatin structure, are induced by replication inhibitors, and encompass much larger regions (100s-1000s of kilobases) it has been more difficult to define particular sequence elements responsible for fragility. However recent progress reviewed here in understanding the link between replication and fragility, as well as identification of proteins and conditions needed to prevent chromosome fragility, have shed some light onto the reasons for breakage at common fragile sites. In addition, the discovery of several types of natural fragile sites on yeast chromosomes and the characterization of associated deletions, duplications, and translocations, has revealed potential mechanisms for fragility and for the chromosomal rearrangements that follow. An understanding of these events will provide insight into the generation of cancer, since deletions and rearrangements at human common fragile sites and associated tumor suppressor genes are an early event in tumorigenesis.

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Recombination at Collapsed Replication Forks: the Payoff for Survival

Abstract: Recombination is believed to assist replication when forks collapse. By using an elegant system, Lambert et al. (2005) address the consequences of recombination at blocked forks. They show that chromosomal rearrangements are the price to pay for cell viability when forks collapse.

Cited by 5 publications

References 10 publications

Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants

Chromatin architecture changes and DNA replication fork collapse are critical features in cryopreserved cells that are differentially controlled by cryoprotectants

Localization of recombination proteins and Srs2 reveals anti-recombinase function in vivo

Chromosome fragility: molecular mechanisms and cellular consequences

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