Folate deficiency drives mitotic missegregation of the human
            <i>FRAXA</i>
            locus

Bjerregaard, Victoria A.; Garribba, Lorenza; McMurray, Cynthia T.; Hickson, Ian D.; Liu, Ying

doi:10.1073/pnas.1808377115

Cited by 27 publications

(50 citation statements)

References 44 publications

(61 reference statements)

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“…However, in those cases where MiDAS does not occur and replication at FRAXA fails to be completed, the FRAXA locus would not display overt fragility, but would be missegregated in anaphase. Subsequently, this can lead to FRAXA exclusion into micronuclei in the daughter cells, or trigger the abortion of cytokinesis and the formation of a tetraploid progeny, as described previously (26). It remains unclear why some of the fragile FRAXA loci seemingly fail to activate MiDAS at all.…”

Section: Discussionmentioning

confidence: 89%

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Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells

Garribba

Bjerregaard

Dinis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Folate deprivation drives the instability of a group of rare fragile sites (RFSs) characterized by CGG trinucleotide repeat (TNR) sequences. Pathological expansion of the TNR within theFRAXAlocus perturbs DNA replication and is the major causative factor for fragile X syndrome, a sex-linked disorder associated with cognitive impairment. Although folate-sensitive RFSs share many features with common fragile sites (CFSs; which are found in all individuals), they are induced by different stresses and share no sequence similarity. It is known that a pathway (termed MiDAS) is employed to complete the replication of CFSs in early mitosis. This process requires RAD52 and is implicated in generating translocations and copy number changes at CFSs in cancers. However, it is unclear whether RFSs also utilize MiDAS and to what extent the fragility of CFSs and RFSs arises by shared or distinct mechanisms. Here, we demonstrate that MiDAS does occur atFRAXAfollowing folate deprivation but proceeds via a pathway that shows some mechanistic differences from that at CFSs, being dependent on RAD51, SLX1, and POLD3. A failure to complete MiDAS atFRAXAleads to severe locus instability and missegregation in mitosis. We propose that break-induced DNA replication is required for the replication ofFRAXAunder folate stress and define a cellular function for human SLX1. These findings provide insights into how folate deprivation drives instability in the human genome.

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Section: Discussionmentioning

confidence: 89%

“…We analyzed previously the segregation of mutant FRAXA loci in mitosis when cells are cultured under "folate stress" conditions (26). That study indicated that folate stress promotes mitotic abnormalities similar to those observed at CFSs, including an increased frequency of chromatin bridges and UFBs.…”

Section: Significancementioning

confidence: 99%

Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells

Garribba

Bjerregaard

Dinis

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…This is common for late replicating fragile sites, like the CGG repeat in the FMR1 promoter (348). In this scenario, ssDNA regions transform into anaphase bridges, which may lead a permanent loss of a part of or even a whole chromosome (261,341).…”

Section: Direct Evidence That Expandable Repeats Are Hard To Replicatementioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

230

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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“…Such correlations could, at least in part, be mediated by the deregulation of FRAXA-residing, DSB repair-inhibiting miRNA genes, and have an impact on cancer progression. These features, combined with the fact that the FRAXA region is prone to a loss of genomic integrity, e.g., gaps, breaks, rearrangements or translocations [45,73,74], lead to the postulation that an alteration at this particular FS stands increased chances of deregulation of the proximal miRNA genes. This, in turn, might disturb the levels of components of the DSB repair pathways.…”

Section: Fraxa Is a Conserved Hotspot For Mirna Genes Inhibiting Compmentioning

confidence: 99%

“…In detail, folate deficiency causes replication-associated DNA breakage and wide-spread genomic instability, and FRAXA belongs to the category of RFS which are particularly sensitive to folate deprivation, especially when CGG trinucleotide repeats in the FMR1 gene expand beyond a critical size. Characteristics of FRAXA site that contribute to its instability are proposed to be (a) atypical DNA structures formed by the CGG repeat itself and (b) defective mitotic sister chromatid disjunction of genomic regions containing long CGG repeats [73]. The existence of FX-miR clusters that target DSB repair pathways upstream of the site of formation of long CGG repeats provides new insights on how genome instability could be spread.…”

Section: Fraxa Is a Conserved Hotspot For Mirna Genes Inhibiting Compmentioning

confidence: 99%

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

Marquardt

Richter

Pützer

et al. 2020

Cancers

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Double strand break (DSB) repair mechanisms guard genome integrity and their deterioration causes genomic instability. Common and rare fragile sites (CFS and RFS, respectively) are particularly vulnerable to instability, and there is an inverse correlation between fragile site (FS) expression and DSB repair protein levels. Upon DSB repair dysfunction, genes residing at these sites are at greater risk of deregulation compared to genes located at non-FS. In this regard, it remains enigmatic why the incidence of miRNA genes at FS is higher compared to non-FS. Herein, using bioinformatics, we examined whether miRNA genes localized at FS inhibit components of DSB repair pathways and assessed their effects on cancer. We show that such miRNAs over-accumulate in RFS, and that FRAXA, which is expressed in Fragile X syndrome, is a conserved hotspot for miRNAs inhibiting DSB repair. Axes of FRAXA-residing miRNAs/DSB repair targets affect survival in a cancer type-specific manner. Moreover, copy number variations in the region encompassing these miRNA genes discriminate survival between male and female patients. Given that, thus far, only CFS have been considered relevant for carcinogenesis, our data are the first to associate RFS with cancer, through the impairment of DSB repair by the FRAXA-residing miRNAs.

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Folate deficiency drives mitotic missegregation of the human FRAXA locus

Cited by 27 publications

References 44 publications

Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells

Folate stress induces SLX1- and RAD51-dependent mitotic DNA synthesis at the fragile X locus in human cells

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

MiRNAs Targeting Double Strand DNA Repair Pathways Lurk in Genomically Unstable Rare Fragile Sites and Determine Cancer Outcomes

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