Faculty Opinions recommendation of Identification of early replicating fragile sites that contribute to genome instability.

Chromosomal fragile sites are implicated in promoting genome instability, which drives cancers and neurological diseases. Yet, the causes and mechanisms of chromosome fragility remain speculative. Here, we identify three spontaneous fragile sites in the Escherichia coli genome and define their DNA damage and repair intermediates at high resolution. We find that all three sites, all in the region of replication termination, display recurrent four-way DNA or Holliday junctions (HJs) and recurrent DNA breaks. Homology-directed double-strand break repair generates the recurrent HJs at all of these sites; however, distinct mechanisms of DNA breakage are implicated: replication fork collapse at natural replication barriers and, unexpectedly, frequent shearing of unsegregated sister chromosomes at cell division. We propose that mechanisms such as both of these may occur ubiquitously, including in humans, and may constitute some of the earliest events that underlie somatic cell mosaicism, cancers, and other diseases of genome instability.

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FANCD2 tunes the UPR preventing mitochondrial stress-induced common fragile site instability

10.1101/808915 ◽

2019 ◽

Author(s):

Philippe Fernandes ◽

Benoit Miotto ◽

Claude Saint-Ruf ◽

Viola Nähse ◽

Silvia Ravera ◽

...

Keyword(s):

Gene Expression ◽

Genome Instability ◽

Fragile Site ◽

Transcriptional Response ◽

Genomic Analysis ◽

Fragile Sites ◽

The Unfolded Protein Response ◽

And Function ◽

Large Genes ◽

Genomic Regions

AbstractCommon fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability relies on transcription- and replication-dependent mechanisms. Here, we uncover a role for the UBL5-dependent branch of the unfolded protein response pathway (UPR) in the maintenance of CFS stability. We show that genetic or pharmacological UPR activation induces CFS gene expression and concomitant relocalization of FANCD2, a master regulator of CFS stability, to CFSs. Furthermore, a genomic analysis of FANCD2 binding sites identified an enrichment for mitochondrial UPR transcriptional response elements in FANCD2 bound regions. We demonstrated that depletion of FANCD2 increases CFS gene transcription and their instability while also inducing mitochondrial dysfunction and triggering the activation of the UPR pathway. Depletion of UBL5, a mediator of the UPR, but not ATF4, reduces CFS gene expression and breakage in FANCD2-depleted cells. We thus demonstrate that FANCD2 recruitment and function at CFSs depends on transcription and UPR signaling, and in absence of transcription or UBL5, FANCD2 is dispensable for CFS stability. We propose that FANCD2 coordinates nuclear and mitochondrial activities by tuning the UPR to prevent genome instability.

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Mammalian DNA Polymerase Kappa Activity and Specificity

Molecules ◽

10.3390/molecules24152805 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2805 ◽

Cited By ~ 6

Author(s):

Hannah R. Stern ◽

Jana Sefcikova ◽

Victoria E. Chaparro ◽

Penny J. Beuning

Keyword(s):

Dna Polymerase ◽

Genome Instability ◽

Fragile Sites ◽

Chemotherapy Response ◽

Nucleotide Polymorphisms ◽

Lesion Bypass ◽

Base Pairs ◽

Domains Of Life ◽

Copy Dna ◽

Y Family

DNA polymerase (pol) kappa is a Y-family translesion DNA polymerase conserved throughout all domains of life. Pol kappa is special6 ized for the ability to copy DNA containing minor groove DNA adducts, especially N2-dG adducts, as well as to extend primer termini containing DNA damage or mismatched base pairs. Pol kappa generally cannot copy DNA containing major groove modifications or UV-induced photoproducts. Pol kappa can also copy structured or non-B-form DNA, such as microsatellite DNA, common fragile sites, and DNA containing G quadruplexes. Thus, pol kappa has roles both in maintaining and compromising genomic integrity. The expression of pol kappa is altered in several different cancer types, which can lead to genome instability. In addition, many cancer-associated single-nucleotide polymorphisms have been reported in the POLK gene, some of which are associated with poor survival and altered chemotherapy response. Because of this, identifying inhibitors of pol kappa is an active area of research. This review will address these activities of pol kappa, with a focus on lesion bypass and cellular mutagenesis.

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Faculty Opinions recommendation of Identification of early replicating fragile sites that contribute to genome instability.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717973332.793471171 ◽

2013 ◽

Author(s):

Olivier Hyrien

Keyword(s):

Genome Instability ◽

Fragile Sites

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Common chromosome fragile sites in human and murine epithelial cells andFHIT/FRA3Bloss-induced global genome instability

Genes Chromosomes and Cancer ◽

10.1002/gcc.22097 ◽

2013 ◽

Vol 52 (11) ◽

pp. 1017-1029 ◽

Cited By ~ 39

Author(s):

Seyed Ali Hosseini ◽

Susan Horton ◽

Joshua C. Saldivar ◽

Satoshi Miuma ◽

Martha R. Stampfer ◽

...

Keyword(s):

Epithelial Cells ◽

Genome Instability ◽

Fragile Sites

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Repetitive Fragile Sites: Centromere Satellite DNA As a Source of Genome Instability in Human Diseases

Genes ◽

10.3390/genes9120615 ◽

2018 ◽

Vol 9 (12) ◽

pp. 615 ◽

Cited By ~ 25

Author(s):

Elizabeth M. Black ◽

Simona Giunta

Keyword(s):

Satellite Dna ◽

Genome Instability ◽

Fragile Sites ◽

Special Focus ◽

Alpha Satellite ◽

Chromosomal Locus ◽

Alpha Satellite Dna ◽

Human Centromere ◽

Repetitive Nature ◽

Human Genome Assembly

Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency–centromeric instability–facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats’ role in physiology and beyond.

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