The complex basis underlying common fragile site instability in cancer

Ozeri-Galai, Efrat; Bester, Assaf C.; Kerem, Batsheva

doi:10.1016/j.tig.2012.02.006

Cited by 76 publications

(79 citation statements)

References 96 publications

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“…At an engineered replication fork stalling site in mammalian cells mutant for BRCA1 or BRCA2, a high frequency of long-tract gene conversions, similar to the long-tract gene conversions reported here at fragile site FS2, was observed (Willis et al 2014;Willis and Scully 2016). Replication difficulty is a hallmark feature of human common fragile sites, and these sites are frequently implicated in genomic alterations in tumors (Burrow et al 2009;Bignell et al 2010;Ozeri-Galai et al 2012). These data together with the results presented here suggest that BIR-like mechanisms are likely to be responsible for copy number changes and rearrangements at fragile sites in tumors, and we propose that instability at common fragile sites may also drive LOH in cancer through dBIR-mediated long-tract gene conversion.…”

Section: Relevance To Genomic Alterations At Human Common Fragile Sitsupporting

confidence: 64%

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Chumki¹,

Dunn²,

Coates³

et al. 2016

Genetics

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Replication stress causes breaks at chromosomal locations called common fragile sites. Deletions causing loss of heterozygosity (LOH) in human tumors are strongly correlated with common fragile sites, but the role of gene conversion in LOH at fragile sites in tumors is less well studied. Here, we investigated gene conversion stimulated by instability at fragile site FS2 in the yeast Saccharomyces cerevisiae. In our screening system, mitotic LOH events near FS2 are identified by production of red/white sectored colonies. We analyzed single nucleotide polymorphisms between homologs to determine the cause and extent of LOH. Instability at FS2 increases gene conversion 48-to 62-fold, and conversions unassociated with crossover represent 6-7% of LOH events. Gene conversion can result from repair of mismatches in heteroduplex DNA during synthesis-dependent strand annealing (SDSA), double-strand break repair (DSBR), and from break-induced replication (BIR) that switches templates [double BIR (dBIR)]. It has been proposed that SDSA and DSBR typically result in shorter gene-conversion tracts than dBIR. In cells under replication stress, we found that bidirectional tracts at FS2 have a median length of 40.8 kb and a wide distribution of lengths; most of these tracts are not crossover-associated. Tracts that begin at the fragile site FS2 and extend only distally are significantly shorter. The high abundance and long length of noncrossover, bidirectional gene-conversion tracts suggests that dBIR is a prominent mechanism for repair of lesions at FS2, thus this mechanism is likely to be a driver of common fragile site-stimulated LOH in human tumors.KEYWORDS loss of heterozygosity; gene conversion; BIR; fragile site; homologous recombination D NA integrity is frequently challenged by chemical, environmental, and physical agents, as well as by endogenous factors. Common fragile sites are one source of endogenous damage, causing DNA instability and breaks under conditions of replication stress when DNA replication is partially inhibited (Durkin and Glover 2007;Sarni and Kerem 2016). Replication stress has typically been induced experimentally by treating cells with the polymerase inhibitor aphidicolin (Glover et al. 1984) or by genetically lowering the levels of DNA polymerases Lemoine et al. 2008). In vivo, replication stress has been observed early in the process of tumor development as a result of alteration of replication fork progression and nucleotide deficiency caused by activation of oncogenes (Di Micco et al. 2006;Bester et al. 2011). In cancer cells, human common fragile sites are hotspots for chromosomal deletions, amplifications, and rearrangements (Burrow et al. 2009;Drusco et al. 2011; OzeriGalai et al. 2011 OzeriGalai et al. , 2012, and a large-scale screen of deletions in 746 cancer cell lines reported that many areas of unexplained deletions are in fragile sites (Bignell et al. 2010).The alterations at human common fragile sites in cancer cells are proposed to result from the processes of DNA repair at...

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Section: Relevance To Genomic Alterations At Human Common Fragile Sitsupporting

confidence: 64%

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Chumki¹,

Dunn²,

Coates³

et al. 2016

Genetics

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“…Other, yet undetermined, processes affected by oncogene overexpression could be epigenetic changes affecting, for example, the regulation of origins of replication. Abundance and initiation programs of origins of replications have been shown to set FS fragility 29 . Thus, changes affecting origin regulation and setting are likely to underlie changes in the landscape of fragility following oncogene overexpression.…”

Section: Discussionmentioning

confidence: 99%

Oncogenes create a unique landscape of fragile sites

et al. 2015

Self Cite

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Recurrent genomic instability in cancer is attributed to positive selection and/or the sensitivity of specific genomic regions to breakage. Among these regions are fragile sites (FSs), genomic regions sensitive to replication stress conditions induced by the DNA polymerase inhibitor aphidicolin. However, the basis for the majority of cancer genomic instability hotspots remains unclear. Aberrant oncogene expression induces replication stress, leading to DNA breaks and genomic instability. Here we map the cytogenetic locations of oncogene-induced FSs and show that in the same cells, each oncogene creates a unique fragility landscape that only partially overlaps with aphidicolin-induced FSs. Oncogene-induced FSs colocalize with cancer breakpoints and large genes, similar to aphidicolin-induced FSs. The observed plasticity in the fragility landscape of the same cell type following oncogene expression highlights an additional level of complexity in the molecular basis for recurrent fragility in cancer.

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“…Cite this article as Cold Spring Harb Perspect Biol 2015;7:a015792 during mitosis, in particular, following replication stress (reviewed by Debatisse et al 2011;Ozeri-Galai et al 2012). In this class of UFBs (Fig.…”

Section: Mitotic Chromosome Dynamicsmentioning

confidence: 99%

Chromosome Dynamics during Mitosis

Hirano

2015

Cold Spring Harb Perspect Biol

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The primary goal of mitosis is to partition duplicated chromosomes into daughter cells. Eukaryotic chromosomes are equipped with two distinct classes of intrinsic machineries, cohesin and condensins, that ensure their faithful segregation during mitosis. Cohesin holds sister chromatids together immediately after their synthesis during S phase until the establishment of bipolar attachments to the mitotic spindle in metaphase. Condensins, on the other hand, attempt to "resolve" sister chromatids by counteracting cohesin. The products of the balancing acts of cohesin and condensins are metaphase chromosomes, in which two rod-shaped chromatids are connected primarily at the centromere. In anaphase, this connection is released by the action of separase that proteolytically cleaves the remaining population of cohesin. Recent studies uncover how this series of events might be mechanistically coupled with each other and intricately regulated by a number of regulatory factors.

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The complex basis underlying common fragile site instability in cancer

Cited by 76 publications

References 96 publications

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Remarkably Long-Tract Gene Conversion Induced by Fragile Site Instability inSaccharomyces cerevisiae

Oncogenes create a unique landscape of fragile sites

Chromosome Dynamics during Mitosis

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