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  1. Article ; Online: Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination.

    Galanti, Lorenzo / Peritore, Martina / Gnügge, Robert / Cannavo, Elda / Heipke, Johannes / Palumbieri, Maria Dilia / Steigenberger, Barbara / Symington, Lorraine S / Cejka, Petr / Pfander, Boris

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 2890

    Abstract: DNA double-strand breaks (DSBs) can be repaired by several pathways. In eukaryotes, DSB repair pathway choice occurs at the level of DNA end resection and is controlled by the cell cycle. Upon cell cycle-dependent activation, cyclin-dependent kinases ( ... ...

    Abstract DNA double-strand breaks (DSBs) can be repaired by several pathways. In eukaryotes, DSB repair pathway choice occurs at the level of DNA end resection and is controlled by the cell cycle. Upon cell cycle-dependent activation, cyclin-dependent kinases (CDKs) phosphorylate resection proteins and thereby stimulate end resection and repair by homologous recombination (HR). However, inability of CDK phospho-mimetic mutants to bypass this cell cycle regulation, suggests that additional cell cycle regulators may be important. Here, we identify Dbf4-dependent kinase (DDK) as a second major cell cycle regulator of DNA end resection. Using inducible genetic and chemical inhibition of DDK in budding yeast and human cells, we show that end resection and HR require activation by DDK. Mechanistically, DDK phosphorylates at least two resection nucleases in budding yeast: the Mre11 activator Sae2, which promotes resection initiation, as well as the Dna2 nuclease, which promotes resection elongation. Notably, synthetic activation of DDK allows limited resection and HR in G1 cells, suggesting that DDK is a key component of DSB repair pathway selection.
    MeSH term(s) Humans ; DNA Breaks, Double-Stranded ; Cell Cycle ; Homologous Recombination ; Cell Division ; Endonucleases/metabolism ; Cyclin-Dependent Kinases/genetics ; Cyclin-Dependent Kinases/metabolism ; DNA ; DNA Repair ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
    Chemical Substances Endonucleases (EC 3.1.-) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; DNA (9007-49-2) ; Saccharomyces cerevisiae Proteins
    Language English
    Publishing date 2024-04-03
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-46951-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Replication fork plasticity upon replication stress requires rapid nuclear actin polymerization.

    Palumbieri, Maria Dilia / Merigliano, Chiara / Acosta, Daniel González / von Känel, Thomas / Welter, Bettina / Stoy, Henriette / Krietsch, Jana / Ulferts, Svenja / Sanchi, Andrea / Grosse, Robert / Chiolo, Irene / Lopes, Massimo

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and ... ...

    Abstract Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase, rapidly extending in number and thickness upon genotoxic treatments, and taking frequent contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork plasticity is linked to reduced recruitment of RAD51 and SMARCAL1 to nascent DNA. Conversely, PRIMPOL gains access to replicating chromatin, promoting unrestrained and discontinuous DNA synthesis, which is associated with increased chromosomal instability and decreased cellular resistance to replication stress. Hence, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.
    Language English
    Publishing date 2023-03-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.24.534097
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity.

    Palumbieri, Maria Dilia / Merigliano, Chiara / González-Acosta, Daniel / Kuster, Danina / Krietsch, Jana / Stoy, Henriette / von Känel, Thomas / Ulferts, Svenja / Welter, Bettina / Frey, Joël / Doerdelmann, Cyril / Sanchi, Andrea / Grosse, Robert / Chiolo, Irene / Lopes, Massimo

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 7819

    Abstract: Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and ... ...

    Abstract Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase and observed their rapid extension in number and length upon genotoxic treatments, frequently taking contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork remodeling is linked to deregulated chromatin loading of PrimPol, which promotes unrestrained and discontinuous DNA synthesis and limits the recruitment of RAD51 and SMARCAL1 to nascent DNA. Moreover, defective nuclear actin polymerization upon mild replication interference induces chromosomal instability in a PRIMPOL-dependent manner. Hence, by limiting PrimPol activity, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.
    MeSH term(s) Actins/genetics ; Polymerization ; Cell Line, Tumor ; DNA Replication ; DNA/genetics
    Chemical Substances Actins ; DNA (9007-49-2)
    Language English
    Publishing date 2023-11-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-43183-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression.

    Giansanti, Celeste / Manzini, Valentina / Dickmanns, Antje / Dickmanns, Achim / Palumbieri, Maria Dilia / Sanchi, Andrea / Kienle, Simon Maria / Rieth, Sonja / Scheffner, Martin / Lopes, Massimo / Dobbelstein, Matthias

    Cell reports

    2022  Volume 39, Issue 9, Page(s) 110879

    Abstract: The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination. However, it also sustains the progression of DNA replication forks, even in the absence of functional p53. Here, we show that MDM2 binds, inhibits, ... ...

    Abstract The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination. However, it also sustains the progression of DNA replication forks, even in the absence of functional p53. Here, we show that MDM2 binds, inhibits, ubiquitinates, and destabilizes poly(ADP-ribose) polymerase 1 (PARP1). When cellular MDM2 levels are increased, this leads to accelerated progression of DNA replication forks, much like pharmacological inhibition of PARP1. Conversely, overexpressed PARP1 restores normal fork progression despite elevated MDM2. Strikingly, MDM2 profoundly reduces the frequency of fork reversal, revealed as four-way junctions through electron microscopy. Depletion of RECQ1 or the primase/polymerase (PRIMPOL) reverses the MDM2-mediated acceleration of the nascent DNA elongation rate. MDM2 also increases the occurrence of micronuclei, and it exacerbates camptothecin-induced cell death. In conclusion, high MDM2 levels phenocopy PARP inhibition in modulation of fork restart, representing a potential vulnerability of cancer cells.
    MeSH term(s) DNA/genetics ; DNA Damage ; DNA Primase/metabolism ; DNA Replication ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Tumor Suppressor Protein p53 ; DNA (9007-49-2) ; DNA Primase (EC 2.7.7.-)
    Language English
    Publishing date 2022-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2022.110879
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Sequential role of RAD51 paralog complexes in replication fork remodeling and restart.

    Berti, Matteo / Teloni, Federico / Mijic, Sofija / Ursich, Sebastian / Fuchs, Jevgenij / Palumbieri, Maria Dilia / Krietsch, Jana / Schmid, Jonas A / Garcin, Edwige B / Gon, Stéphanie / Modesti, Mauro / Altmeyer, Matthias / Lopes, Massimo

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 3531

    Abstract: Homologous recombination (HR) factors were recently implicated in DNA replication fork remodeling and protection. While maintaining genome stability, HR-mediated fork remodeling promotes cancer chemoresistance, by as-yet elusive mechanisms. Five HR ... ...

    Abstract Homologous recombination (HR) factors were recently implicated in DNA replication fork remodeling and protection. While maintaining genome stability, HR-mediated fork remodeling promotes cancer chemoresistance, by as-yet elusive mechanisms. Five HR cofactors - the RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3 - recently emerged as crucial tumor suppressors. Albeit extensively characterized in DNA repair, their role in replication has not been addressed systematically. Here, we identify all RAD51 paralogs while screening for modulators of RAD51 recombinase upon replication stress. Single-molecule analysis of fork progression and architecture in isogenic cellular systems shows that the BCDX2 subcomplex restrains fork progression upon stress, promoting fork reversal. Accordingly, BCDX2 primes unscheduled degradation of reversed forks in BRCA2-defective cells, boosting genomic instability. Conversely, the CX3 subcomplex is dispensable for fork reversal, but mediates efficient restart of reversed forks. We propose that RAD51 paralogs sequentially orchestrate clinically relevant transactions at replication forks, cooperatively promoting fork remodeling and restart.
    MeSH term(s) BRCA2 Protein/metabolism ; Cell Line, Tumor ; Chromosome Structures/metabolism ; Chromosomes/ultrastructure ; DNA Damage ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/metabolism ; Genomic Instability ; Homologous Recombination ; Humans ; Microscopy ; Mutagens ; Mutation ; Osteosarcoma/metabolism ; RNA, Small Interfering/metabolism ; Rad51 Recombinase/metabolism
    Chemical Substances BRCA2 Protein ; BRCA2 protein, human ; DNA-Binding Proteins ; Mutagens ; RAD51B protein, human ; RAD51C protein, human ; RAD51D protein, human ; RNA, Small Interfering ; X-ray repair cross complementing protein 3 ; XRCC2 protein, human ; RAD51 protein, human (EC 2.7.7.-) ; Rad51 Recombinase (EC 2.7.7.-)
    Language English
    Publishing date 2020-07-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-17324-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Intra-epithelial non-canonical Activin A signaling safeguards prostate progenitor quiescence.

    Cambuli, Francesco / Foletto, Veronica / Alaimo, Alessandro / De Felice, Dario / Gandolfi, Francesco / Palumbieri, Maria Dilia / Zaffagni, Michela / Genovesi, Sacha / Lorenzoni, Marco / Celotti, Martina / Bertossio, Emiliana / Mazzero, Giosuè / Bertossi, Arianna / Bisio, Alessandra / Berardinelli, Francesco / Antoccia, Antonio / Gaspari, Marco / Barbareschi, Mattia / Fiorentino, Michelangelo /
    Shen, Michael M / Loda, Massimo / Romanel, Alessandro / Lunardi, Andrea

    EMBO reports

    2022  Volume 23, Issue 5, Page(s) e54049

    Abstract: The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during aging, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-β ligands have been known to induce ... ...

    Abstract The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during aging, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-β ligands have been known to induce cytostasis in a variety of epithelia, but the intracellular pathway mediating this signal in the prostate, and its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we find that intra-epithelial non-canonical Activin A signaling inhibits cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggers Tak1 and p38 ΜAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurs upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro are also able to implant with increased frequency into immunocompetent mice. This study demonstrates that non-canonical Activin A signaling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumor progenitors.
    MeSH term(s) Activins/metabolism ; Animals ; Male ; Mice ; Prostate/metabolism ; Signal Transduction ; Transforming Growth Factor beta/metabolism
    Chemical Substances Transforming Growth Factor beta ; activin A ; Activins (104625-48-1)
    Language English
    Publishing date 2022-03-07
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202154049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5433: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
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  7. Article ; Online: An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer.

    Chen, Ming / Zhang, Jiangwen / Sampieri, Katia / Clohessy, John G / Mendez, Lourdes / Gonzalez-Billalabeitia, Enrique / Liu, Xue-Song / Lee, Yu-Ru / Fung, Jacqueline / Katon, Jesse M / Menon, Archita Venugopal / Webster, Kaitlyn A / Ng, Christopher / Palumbieri, Maria Dilia / Diolombi, Moussa S / Breitkopf, Susanne B / Teruya-Feldstein, Julie / Signoretti, Sabina / Bronson, Roderick T /
    Asara, John M / Castillo-Martin, Mireia / Cordon-Cardo, Carlos / Pandolfi, Pier Paolo

    Nature genetics

    2018  Volume 50, Issue 2, Page(s) 206–218

    Abstract: Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse ...

    Abstract Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.
    MeSH term(s) Animals ; Cell Line, Tumor ; Cell Proliferation/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Humans ; Lipogenesis/genetics ; Male ; Metabolic Networks and Pathways/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasm Metastasis ; PC-3 Cells ; PTEN Phosphohydrolase/genetics ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Sterol Regulatory Element Binding Proteins/genetics ; Sterol Regulatory Element Binding Proteins/physiology
    Chemical Substances Sterol Regulatory Element Binding Proteins ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67)
    Language English
    Publishing date 2018-01-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-017-0027-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3613: Show issues Location:
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