Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Franchitto, Annapaola; Pichierri, Pietro

doi:10.4161/cc.10.23.18409

Cited by 24 publications

(24 citation statements)

References 86 publications

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“…Unlike in the entire genome, additional origins in FRA16C region are not activated under mild replication stress, leading ultimately to the failure of normal replication completion in the FRA16C region [37]. It is now increasingly clear that failure of origin activation is a common feature of CFSs [38,39]. Therefore, CFS fragility is caused either by perturbed fork progression at AT-dinucleotide repeats that form stable secondary structures, or by an intrinsic paucity of replicating origins along a CFS.…”

Section: Mechanisms Of Cfs Instabilitymentioning

confidence: 99%

Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis

Qiu

Mrasek

et al. 2012

IJMS

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Genomic instability, a hallmark of cancer, occurs preferentially at specific genomic regions known as common fragile sites (CFSs). CFSs are evolutionarily conserved and late replicating regions with AT-rich sequences, and CFS instability is correlated with cancer. In the last decade, much progress has been made toward understanding the mechanisms of chromosomal instability at CFSs. However, despite tremendous efforts, identifying a cancer-associated CFS gene (CACG) remains a challenge and little is known about the function of CACGs at most CFS loci. Recent studies of FATS (for Fragile-site Associated Tumor Suppressor), a new CACG at FRA10F, reveal an active role of this CACG in regulating DNA damage checkpoints and suppressing tumorigenesis. The identification of FATS may inspire more discoveries of other uncharacterized CACGs. Further elucidation of the biological functions and clinical significance of CACGs may be exploited for cancer biomarkers and therapeutic benefits.

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Section: Mechanisms Of Cfs Instabilitymentioning

confidence: 99%

Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis

Qiu

Mrasek

et al. 2012

IJMS

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“…Proteins involved in this response (i.e., BRCA1, FANCD2, SMC1, HUS1, CHK1) maintain the stability of difficult to replicate genomic regions known as common fragile sites (CFS). [9][10][11] Hereditary defects in the components of HR-mediated DNA repair pathway or the presence of the mutator phenotype, as exemplified in WRN, BLM, and BRCA1/2 mutant patients, cause genomic breakage at fragile sites and lead to both chromosomal rearrangement and genomic instability. 12,13 Loss of function of breast cancer suppressor gene BRCA2 results in defective HR and triggers genomic instability, thereby accelerating breast cancer tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

ZNF365 promotes stalled replication forks recovery to maintain genome stability

et al. 2013

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The ZNF365 locus is associated with breast cancer risk in carriers of mutated BRCA1 and BRCA2, which are important molecules required for DNA damage response. Previously, we demonstrated that ZNF365 is necessary for timely resolution of replication intermediates of genomic fragile sites and, thus, for suppression of genomic instability; however, the mechanism underlying the function of ZNF365 on damaged DNA and stalled replication forks remains unknown. Here, we demonstrate that ZNF365 is induced by DNA double-strand break (DSB) signals, is involved in the homologous recombination (HR) repair pathway, and maintains genome integrity during DNA replication. On the mechanistic level, ZNF365 interacts with poly(ADP-ribose) polymerase (PARP) 1 to tether MRE11 to the DNA end resection site. Loss of ZNF365 results in delayed mitotic progression and exit due to increased replication stress, ultimately leading to cytokinesis failure, re-duplication of centrosomes, and increased aneuploidy. Collectively, these results suggest an HR repair-dependent function of ZNF365 in preventing genomic instability.

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“…Of clinical significance, breakpoints of chromosomal translocations and deletions in several tumor types have been mapped to CFS 1; 3; 4 . A large number of studies have shown that loss of specific replication, cell cycle checkpoint and DNA repair proteins leads to CFS instability 1; 5; 6; 7 . These findings suggest that maintenance of CFS stability in normal cells requires DNA replication checkpoint and repair responses.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Replicative DNA Polymerase Delta Pausing and a Potential Role for DNA Polymerase Kappa in Common Fragile Site Replication

Walsh

Wang

Lee

et al. 2013

Journal of Molecular Biology

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Common fragile sites (CFS) are hotspots of chromosomal breakage, and CFS breakage models involve perturbations of DNA replication. Here, we analyzed the contribution of specific repetitive DNA sequence elements within CFS to the inhibition of DNA synthesis by replicative and specialized DNA polymerases. The efficiency of in vitro DNA synthesis was quantitated using templates corresponding to regions within FRA16D and FRA3B harboring AT-rich microsatellite and quasi-palindrome (QP) sequences. QPs were predicted to form stems of ~75-100% self homology, separated by 3-9 bases of intervening sequences. Analysis of DNA synthesis progression by human DNA polymerase δ (Pol δ) demonstrated significant synthesis perturbation both at [A]n and [TA]n repeats in a length-dependent manner, and at short (<40 basepairs) QP sequences. DNA synthesis by the Y-family polymerase κ was significantly more efficient than Pol δ through both types of repetitive elements. Using DNA trap experiments, we show that Pol δ pauses within CFS sequences are sites of enzyme dissociation, and dissociation was observed in the presence of RFC-loaded PCNA. We propose that enrichment of microsatellite and QP elements at CFS regions contributes to fragility by perturbing replication through multiple mechanisms, including replicative DNA polymerase pausing and dissociation. Our finding that Pol δ dissociates at specific CFS sequences is significant, since dissociation of the replication machinery and inability to efficiently recover the replication fork can lead to fork collapse and/or formation of double-strand breaks in vivo. Our biochemical studies also extend the potential involvement of Y-family polymerases in CFS maintenance to include polymerase κ.

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Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Cited by 24 publications

References 86 publications

Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis

Common Fragile Sites: Genomic Hotspots of DNA Damage and Carcinogenesis

ZNF365 promotes stalled replication forks recovery to maintain genome stability

Mechanism of Replicative DNA Polymerase Delta Pausing and a Potential Role for DNA Polymerase Kappa in Common Fragile Site Replication

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