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  1. Article ; Online: Corrigendum to "PARP Activity Fine-tunes the DNA Replication Choreography of Chk1-depleted Cells" [J. Mol. Biol. 433(10) (2021) 166949].

    Calzetta, Nicolás Luis / González Besteiro, Marina Alejandra / Gottifredi, Vanesa

    Journal of molecular biology

    2023  Volume 435, Issue 23, Page(s) 168311

    Language English
    Publishing date 2023-10-18
    Publishing country Netherlands
    Document type Published Erratum
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2023.168311
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
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  2. Article ; Online: PARP Activity Fine-tunes the DNA Replication Choreography of Chk1-depleted Cells.

    Calzetta, Nicolás Luis / González Besteiro, Marina Alejandra / Gottifredi, Vanesa

    Journal of molecular biology

    2021  Volume 433, Issue 10, Page(s) 166949

    Abstract: Checkpoint Kinase 1 (Chk1) prevents DNA damage by adjusting the replication choreography in the face of replication stress. Chk1 depletion provokes slow and asymmetrical fork movement, yet the signals governing such changes remain unclear. We sought to ... ...

    Abstract Checkpoint Kinase 1 (Chk1) prevents DNA damage by adjusting the replication choreography in the face of replication stress. Chk1 depletion provokes slow and asymmetrical fork movement, yet the signals governing such changes remain unclear. We sought to investigate whether poly(ADP-ribose) polymerases (PARPs), key players of the DNA damage response, intervene in the DNA replication of Chk1-depleted cells. We demonstrate that PARP inhibition selectively alleviates the reduced fork elongation rates, without relieving fork asymmetry in Chk1-depleted cells. While the contribution of PARPs to fork elongation is not unprecedented, we found that their role in Chk1-depleted cells extends beyond fork movement. PARP-dependent fork deceleration induced mild dormant origin firing upon Chk1 depletion, augmenting the global rates of DNA synthesis. Thus, we have identified PARPs as novel regulators of replication fork dynamics in Chk1-depleted cells.
    MeSH term(s) Cell Line, Tumor ; Checkpoint Kinase 1/antagonists & inhibitors ; Checkpoint Kinase 1/genetics ; Checkpoint Kinase 1/metabolism ; DNA Replication ; Gene Expression Regulation ; Humans ; Osteoblasts/cytology ; Osteoblasts/drug effects ; Osteoblasts/enzymology ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Kinase Inhibitors/pharmacology ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Roscovitine/pharmacology ; Thymidine/analogs & derivatives ; Thymidine/pharmacology
    Chemical Substances Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; RNA, Small Interfering ; Roscovitine (0ES1C2KQ94) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Thymidine (VC2W18DGKR) ; olaparib (WOH1JD9AR8)
    Language English
    Publishing date 2021-03-18
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2021.166949
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
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  3. Article ; Online: Mus81-Eme1-dependent aberrant processing of DNA replication intermediates in mitosis impairs genome integrity.

    Calzetta, Nicolás Luis / González Besteiro, Marina Alejandra / Gottifredi, Vanesa

    Science advances

    2020  Volume 6, Issue 50

    Abstract: Chromosome instability (CIN) underpins cancer evolution and is associated with drug resistance and poor prognosis. Understanding the mechanistic basis of CIN is thus a priority. The structure-specific endonuclease Mus81-Eme1 is known to prevent CIN. ... ...

    Abstract Chromosome instability (CIN) underpins cancer evolution and is associated with drug resistance and poor prognosis. Understanding the mechanistic basis of CIN is thus a priority. The structure-specific endonuclease Mus81-Eme1 is known to prevent CIN. Intriguingly, however, here we show that the aberrant processing of late replication intermediates by Mus81-Eme1 is a source of CIN. Upon depletion of checkpoint kinase 1 (Chk1), Mus81-Eme1 cleaves under-replicated DNA engaged in mitotic DNA synthesis, leading to chromosome segregation defects. Supplementing cells with nucleosides allows the completion of mitotic DNA synthesis, restraining Mus81-Eme1-dependent DNA damage in mitosis and the ensuing CIN. We found no correlation between CIN arising from nucleotide shortage in mitosis and cell death, which were selectively linked to DNA damage load in mitosis and S phase, respectively. Our findings imply the possibility of optimizing Chk1-directed therapies by inducing cell death while curtailing CIN, a common side effect of chemotherapy.
    MeSH term(s) Chromosomal Instability ; DNA/genetics ; DNA Damage ; DNA Replication ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Endodeoxyribonucleases/genetics ; Endodeoxyribonucleases/metabolism ; Endonucleases/genetics ; Endonucleases/metabolism ; Genomic Instability ; Humans ; Mitosis
    Chemical Substances DNA-Binding Proteins ; DNA (9007-49-2) ; Eme1 protein, human (EC 3.1.-) ; Endodeoxyribonucleases (EC 3.1.-) ; Endonucleases (EC 3.1.-) ; MUS81 protein, human (EC 3.1.-)
    Language English
    Publishing date 2020-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abc8257
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  4. Article: PARP Activity Fine-tunes the DNA Replication Choreography of Chk1-depleted Cells

    Calzetta, Nicolás Luis / González Besteiro, Marina Alejandra / Gottifredi, Vanesa

    Journal of molecular biology. 2021 May 14, v. 433, no. 10

    2021  

    Abstract: Checkpoint Kinase 1 (Chk1) prevents DNA damage by adjusting the replication choreography in the face of replication stress. Chk1 depletion provokes slow and asymmetrical fork movement, yet the signals governing such changes remain unclear. We sought to ... ...

    Abstract Checkpoint Kinase 1 (Chk1) prevents DNA damage by adjusting the replication choreography in the face of replication stress. Chk1 depletion provokes slow and asymmetrical fork movement, yet the signals governing such changes remain unclear. We sought to investigate whether poly(ADP-ribose) polymerases (PARPs), key players of the DNA damage response, intervene in the DNA replication of Chk1-depleted cells. We demonstrate that PARP inhibition selectively alleviates the reduced fork elongation rates, without relieving fork asymmetry in Chk1-depleted cells. While the contribution of PARPs to fork elongation is not unprecedented, we found that their role in Chk1-depleted cells extends beyond fork movement. PARP-dependent fork deceleration induced mild dormant origin firing upon Chk1 depletion, augmenting the global rates of DNA synthesis. Thus, we have identified PARPs as novel regulators of replication fork dynamics in Chk1-depleted cells.
    Keywords DNA damage ; DNA replication ; asymmetry ; molecular biology
    Language English
    Dates of publication 2021-0514
    Publishing place Elsevier Ltd
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2021.166949
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 4' 63/108: Show issues

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  5. Article ; Online: Correction: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

    Martino, Julieta / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / Garro, Cintia / Pansa, Maria F / Carbajosa, Sofía / Brown, Aaron C / Bocco, José Luis / Gloger, Israel / Drewes, Gerard / Madauss, Kevin P / Soria, Gastón / Gottifredi, Vanesa

    eLife

    2023  Volume 12

    Language English
    Publishing date 2023-11-14
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.94414
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  6. Article ; Online: CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication.

    Mansilla, Sabrina Florencia / de la Vega, María Belén / Calzetta, Nicolás Luis / Siri, Sebastián Omar / Gottifredi, Vanesa

    Genes

    2020  Volume 11, Issue 6

    Abstract: ... ...

    Abstract p21
    MeSH term(s) Cyclin-Dependent Kinase Inhibitor p21/genetics ; Cyclin-Dependent Kinases/genetics ; DNA Replication/genetics ; Humans ; Proliferating Cell Nuclear Antigen/genetics ; Protein Kinase Inhibitors/metabolism ; S Phase/genetics
    Chemical Substances CDKN1A protein, human ; Cyclin-Dependent Kinase Inhibitor p21 ; PCNA protein, human ; Proliferating Cell Nuclear Antigen ; Protein Kinase Inhibitors ; Cyclin-Dependent Kinases (EC 2.7.11.22)
    Language English
    Publishing date 2020-05-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2527218-4
    ISSN 2073-4425 ; 2073-4425
    ISSN (online) 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes11060593
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  7. Article ; Online: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells.

    Martino, Julieta / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / Garro, Cintia / Pansa, Maria F / Carbajosa, Sofía / Brown, Aaron C / Bocco, José Luis / Gloger, Israel / Drewes, Gerard / Madauss, Kevin P / Soria, Gastón / Gottifredi, Vanesa

    eLife

    2023  Volume 12

    Abstract: The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2- ... ...

    Abstract The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.
    MeSH term(s) Anaphase ; DNA Damage ; Mitosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Synthetic Lethal Mutations ; rho-Associated Kinases/antagonists & inhibitors ; BRCA2 Protein/genetics ; Humans
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; rho-Associated Kinases (EC 2.7.11.1) ; BRCA2 Protein
    Language English
    Publishing date 2023-04-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.80254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Correction: Unscheduled MRE11 activity triggers cell death but not chromosome instability in polymerase eta-depleted cells subjected to UV irradiation.

    Federico, María Belén / Siri, Sebastián Omar / Calzetta, Nicolás Luis / Paviolo, Natalia Soledad / de la Vega, María Belén / Martino, Julieta / Campana, María Carolina / Wiesmüller, Lisa / Gottifredi, Vanesa

    Oncogene

    2023  Volume 42, Issue 48, Page(s) 3589

    Language English
    Publishing date 2023-09-27
    Publishing country England
    Document type Published Erratum
    ZDB-ID 639046-8
    ISSN 1476-5594 ; 0950-9232
    ISSN (online) 1476-5594
    ISSN 0950-9232
    DOI 10.1038/s41388-023-02854-9
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2218: Show issues Location:
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  9. Article: CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication

    Mansilla, Sabrina Florencia / De La Vega, María Belén / Calzetta, Nicolás Luis / Siri, Sebastián Omar / Gottifredi, Vanesa

    Genes. 2020 May 28, v. 11, no. 6

    2020  

    Abstract: p21ᵂᵃᶠ/Cᴵᴾ¹ is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and ... ...

    Abstract p21ᵂᵃᶠ/Cᴵᴾ¹ is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.
    Keywords DNA replication ; cell cycle checkpoints ; cyclin-dependent kinase ; gamma radiation ; genomics ; interphase ; irradiation ; neoplasms ; proliferating cell nuclear antigen
    Language English
    Dates of publication 2020-0528
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2527218-4
    ISSN 2073-4425
    ISSN 2073-4425
    DOI 10.3390/genes11060593
    Database NAL-Catalogue (AGRICOLA)

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  10. Article: Persistent double strand break accumulation does not precede cell death in an Olaparib-sensitive BRCA-deficient colorectal cancer cell model.

    Paviolo, Natalia Soledad / Vega, María Belén de la / Pansa, María Florencia / García, Iris Alejandra / Calzetta, Nicolás Luis / Soria, Gastón / Gottifredi, Vanesa

    Genetics and molecular biology

    2019  Volume 43, Issue 1 suppl 1, Page(s) e20190070

    Abstract: The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) ... ...

    Abstract The poly (adenosine diphosphate (ADP)-ribosyl) polymerase inhibitors (PARPi) selectively kill cancer cells with BRCA1 or BRCA2 (BRCA)-mutations. It has been proposed that cell death induction after PARPi depends on unrepaired double strand breaks (DSBs) that accumulate due to the homologous recombination deficiency of BRCA-mutated cells. Such accumulation of DSBs is inferred mainly from the high levels of DNA damage markers like phosphorylated histone H2AX. Herein, we developed a model of isogenic cell lines to show that depletion of BRCA causes PARPi-triggered cell death, replication stress (phosphorylated-H2AX and 53BP1 foci), and genomic instability. However, persistent DSBs accumulation was not detected under the same experimental conditions. Hence, at least in this cellular model, the trigger for cell death in PARPi-treated BRCA-depleted samples is not the accumulation of unrepaired DSBs. Instead, cell death better correlates with a rapid and aberrant resolution of DSBs by error-prone pathways that leads to severe chromosomic aberrations. Therefore, our results suggest that in PARPi-treated BRCA-deficient cells, chromosome aberrations may dually trigger both genomic instability and cell death.
    Language English
    Publishing date 2019-12-13
    Publishing country Brazil
    Document type Journal Article
    ZDB-ID 1445712-x
    ISSN 1678-4685 ; 1415-4757
    ISSN (online) 1678-4685
    ISSN 1415-4757
    DOI 10.1590/1678-4685-GMB-2019-0070
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