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  1. Article ; Online: Genome Instability at Common Fragile Sites

    Annapaola Franchitto

    BioMed Research International, Vol

    Searching for the Cause of Their Instability

    2013  Volume 2013

    Abstract: Common fragile sites (CFS) are heritable nonrandomly distributed loci on human chromosomes that exhibit an increased frequency of chromosomal breakage under conditions of replication stress. They are considered the preferential targets for high genomic ... ...

    Abstract Common fragile sites (CFS) are heritable nonrandomly distributed loci on human chromosomes that exhibit an increased frequency of chromosomal breakage under conditions of replication stress. They are considered the preferential targets for high genomic instability from the earliest stages of human cancer development, and increased chromosome instability at these loci has been observed following replication stress in a subset of human genetic diseases. Despite their biological and medical relevance, the molecular basis of CFS fragility in vivo has not been fully elucidated. At present, different models have been proposed to explain how instability at CFS arises and multiple factors seem to contribute to their instability. However, all these models involve DNA replication and suggest that replication fork stalling along CFS during DNA synthesis is a very frequent event. Consistent with this, the maintenance of CFS stability relies on the ATR-dependent checkpoint, together with a number of proteins promoting the recovery of stalled replication forks. In this review, we discuss mainly the possible causes that threaten the integrity of CFS in the light of new findings, paying particular attention to the role of the S-phase checkpoint.
    Keywords Medicine ; R
    Subject code 500
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: R-Loop-Associated Genomic Instability and Implication of WRN and WRNIP1

    Veronica Marabitti / Pasquale Valenzisi / Giorgia Lillo / Eva Malacaria / Valentina Palermo / Pietro Pichierri / Annapaola Franchitto

    International Journal of Molecular Sciences, Vol 23, Iss 1547, p

    2022  Volume 1547

    Abstract: Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, ... ...

    Abstract Maintenance of genome stability is crucial for cell survival and relies on accurate DNA replication. However, replication fork progression is under constant attack from different exogenous and endogenous factors that can give rise to replication stress, a source of genomic instability and a notable hallmark of pre-cancerous and cancerous cells. Notably, one of the major natural threats for DNA replication is transcription. Encounters or conflicts between replication and transcription are unavoidable, as they compete for the same DNA template, so that collisions occur quite frequently. The main harmful transcription-associated structures are R-loops. These are DNA structures consisting of a DNA–RNA hybrid and a displaced single-stranded DNA, which play important physiological roles. However, if their homeostasis is altered, they become a potent source of replication stress and genome instability giving rise to several human diseases, including cancer. To combat the deleterious consequences of pathological R-loop persistence, cells have evolved multiple mechanisms, and an ever growing number of replication fork protection factors have been implicated in preventing/removing these harmful structures; however, many others are perhaps still unknown. In this review, we report the current knowledge on how aberrant R-loops affect genome integrity and how they are handled, and we discuss our recent findings on the role played by two fork protection factors, the Werner syndrome protein (WRN) and the Werner helicase-interacting protein 1 (WRNIP1) in response to R-loop-induced genome instability.
    Keywords genomic instability ; replication stress ; DNA repair ; RecQ helicases ; R-loops ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 612
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Author Correction

    Eva Malacaria / Giusj Monia Pugliese / Masayoshi Honda / Veronica Marabitti / Francesca Antonella Aiello / Maria Spies / Annapaola Franchitto / Pietro Pichierri

    Nature Communications, Vol 10, Iss 1, Pp 1-

    Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation

    2019  Volume 1

    Abstract: The original version of this Article contained an error in Fig. 2. The immunofluorescence images in panel d were inadvertently replaced with duplicates of those in panel c during final assembly of the figure. This has been corrected in the PDF and HTML ... ...

    Abstract The original version of this Article contained an error in Fig. 2. The immunofluorescence images in panel d were inadvertently replaced with duplicates of those in panel c during final assembly of the figure. This has been corrected in the PDF and HTML versions of the Article.
    Keywords Science ; Q
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Author Correction

    Eva Malacaria / Giusj Monia Pugliese / Masayoshi Honda / Veronica Marabitti / Francesca Antonella Aiello / Maria Spies / Annapaola Franchitto / Pietro Pichierri

    Nature Communications, Vol 10, Iss 1, Pp 1-

    Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation

    2019  Volume 1

    Abstract: The original version of this Article contained an error in Fig. 2. The immunofluorescence images in panel d were inadvertently replaced with duplicates of those in panel c during final assembly of the figure. This has been corrected in the PDF and HTML ... ...

    Abstract The original version of this Article contained an error in Fig. 2. The immunofluorescence images in panel d were inadvertently replaced with duplicates of those in panel c during final assembly of the figure. This has been corrected in the PDF and HTML versions of the Article.
    Keywords Science ; Q
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation

    Eva Malacaria / Giusj Monia Pugliese / Masayoshi Honda / Veronica Marabitti / Francesca Antonella Aiello / Maria Spies / Annapaola Franchitto / Pietro Pichierri

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 19

    Abstract: Stabilisation of stalled replication forks prevents excessive fork reversal and genome instability. Here authors reveal a RAD52-dependent replication fork protection mechanism. ...

    Abstract Stabilisation of stalled replication forks prevents excessive fork reversal and genome instability. Here authors reveal a RAD52-dependent replication fork protection mechanism.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Rad52 prevents excessive replication fork reversal and protects from nascent strand degradation

    Eva Malacaria / Giusj Monia Pugliese / Masayoshi Honda / Veronica Marabitti / Francesca Antonella Aiello / Maria Spies / Annapaola Franchitto / Pietro Pichierri

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 19

    Abstract: Stabilisation of stalled replication forks prevents excessive fork reversal and genome instability. Here authors reveal a RAD52-dependent replication fork protection mechanism. ...

    Abstract Stabilisation of stalled replication forks prevents excessive fork reversal and genome instability. Here authors reveal a RAD52-dependent replication fork protection mechanism.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes

    Giusj Monia Pugliese / Federico Salaris / Valentina Palermo / Veronica Marabitti / Nicolò Morina / Alessandro Rosa / Annapaola Franchitto / Pietro Pichierri

    Disease Models & Mechanisms, Vol 12, Iss

    2019  Volume 10

    Abstract: Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to ... ...

    Abstract Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain the pathophysiology of the disease; however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Here, we generated a conditional SMARCAL1 knockdown model in induced pluripotent stem cells (iPSCs) to mimic conditions associated with the severe form the disease. Using multiple cellular endpoints, we characterized this model for the presence of phenotypes linked to the replication caretaker role of SMARCAL1. Our data show that conditional knockdown of SMARCAL1 in human iPSCs induces replication-dependent and chronic accumulation of DNA damage triggering the DNA damage response. Furthermore, they indicate that accumulation of DNA damage and activation of the DNA damage response correlates with increased levels of R-loops and replication-transcription interference. Finally, we provide evidence that SMARCAL1-deficient iPSCs maintain active DNA damage response beyond differentiation, possibly contributing to the observed altered expression of a subset of germ layer-specific master genes. Confirming the relevance of SMARCAL1 loss for the observed phenotypes, they are prevented or rescued after re-expression of wild-type SMARCAL1 in our iPSC model. In conclusion, our conditional SMARCAL1 knockdown model in iPSCs may represent a powerful model when studying pathogenetic mechanisms of severe Schimke immuno-osseous dysplasia.
    Keywords dna damage ; dna replication ; replication stress ; siod ; ipsc ; Medicine ; R ; Pathology ; RB1-214
    Subject code 612
    Language English
    Publishing date 2019-10-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: CDK1 phosphorylates WRN at collapsed replication forks

    Valentina Palermo / Sara Rinalducci / Massimo Sanchez / Francesca Grillini / Joshua A. Sommers / Robert M. Brosh / Lello Zolla / Annapaola Franchitto / Pietro Pichierri

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 15

    Abstract: End-resection of double strand DNA breaks is essential for pathway choice between non-homologous end-joining and homologous recombination. Here the authors show that phosphorylation of WRN helicase by CDK1 is essential for resection at replication- ... ...

    Abstract End-resection of double strand DNA breaks is essential for pathway choice between non-homologous end-joining and homologous recombination. Here the authors show that phosphorylation of WRN helicase by CDK1 is essential for resection at replication-related breaks.
    Keywords Science ; Q
    Language English
    Publishing date 2016-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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