DDK Has a Primary Role in Processing Stalled Replication Forks to Initiate Downstream Checkpoint Signaling
| العنوان: | DDK Has a Primary Role in Processing Stalled Replication Forks to Initiate Downstream Checkpoint Signaling |
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| المؤلفون: | Yea-Lih Lin, Nanda Kumar Sasi, Flavie Coquel, Jeffrey P. MacKeigan, Michael Weinreich, Philippe Pasero |
| المساهمون: | Michigan State University [East Lansing], Michigan State University System, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Systems Biology, Van Andel Institute [Grand Rapids] |
| المصدر: | Journal of Mammary Gland Biology and Neoplasia Journal of Mammary Gland Biology and Neoplasia, Springer Verlag (Germany), 2018, 20 (10), pp.985-995. ⟨10.1016/j.neo.2018.08.001⟩ Neoplasia (New York, N.Y.) Neoplasia: An International Journal for Oncology Research, Vol 20, Iss 10, Pp 985-995 (2018) |
| بيانات النشر: | HAL CCSD, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Exonuclease, DNA Replication, Cancer Research, Original article, Cell cycle checkpoint, DNA damage, [SDV]Life Sciences [q-bio], HU, Hydroxyurea, DNA, Single-Stranded, Mitosis, Cell Cycle Proteins, Pyrimidinones, Biology, Protein Serine-Threonine Kinases, DDK, CDC7-DBF4 kinase, lcsh:RC254-282, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Minichromosome maintenance, Humans, Dimethyl Sulfoxide, Pyrroles, Piperidones, 030304 developmental biology, Etoposide, Genetics, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kinase, DNA replication, G2-M DNA damage checkpoint, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell biology, CPT, Camptothecin, 030104 developmental biology, DNA Repair Enzymes, Exodeoxyribonucleases, chemistry, 030220 oncology & carcinogenesis, biology.protein, Phosphorylation, DNA, Signal Transduction |
| الوصف: | International audience; CDC7-DBF4 kinase (DDK) initiates DNA replication in eukaryotes by activating the replicative MCM helicase. DDK has diverse and apparently conflicting roles in the replication checkpoint response in various organisms, but the underlying mechanisms are far from settled. We show that human DDK promotes limited resection of newly synthesized DNA at stalled replication forks or sites of DNA damage to initiate replication checkpoint signaling. DDK is also required for efficient fork restart and G2/M cell cycle arrest. DDK exhibits genetic interactions with the ssDNA exonuclease EXO1 and phosphorylates EXO1 in vitro. EXO1 is also required for nascent strand degradation following exposure to HU, so DDK might regulate EXO1 directly. Lastly, sublethal DDK inhibition causes various mitotic abnormalities, which is consistent with a checkpoint deficiency. In summary, DDK has a primary and previously undescribed role in the replication checkpoint to promote ssDNA accumulation at stalled forks, which is required to initiate a robust checkpoint response and cell cycle arrest to maintain genome integrity. |
| اللغة: | English |
| تدمد: | 1083-3021 1573-7039 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8fcdca87b1ea826123e9f5a18c7f3591Test https://hal.archives-ouvertes.fr/hal-01887535Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8fcdca87b1ea826123e9f5a18c7f3591 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10833021 15737039 |
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