title: Tousled-like kinase 2 regulates recovery from a DNA damage-induced G2 arrest.
abstract: In order to maintain a stable genome, cells need to detect and repair DNA damage before they complete the division cycle. To this end, cell cycle checkpoints prevent entry into the next cell cycle phase until the damage is fully repaired. Proper reentry into the cell cycle, known as checkpoint recovery, requires that a cell retains its original cell cycle state during the arrest. Here, we have identified Tousled-like kinase 2 (Tlk2) as an important regulator of recovery after DNA damage in G2. We show that Tlk2 regulates the Asf1A histone chaperone in response to DNA damage and that depletion of Asf1A also produces a recovery defect. Both Tlk2 and Asf1A are required to restore histone H3 incorporation into damaged chromatin. Failure to do so affects expression of pro-mitotic genes and compromises the cellular competence to recover from damage-induced cell cycle arrests. Our results demonstrate that Tlk2 promotes Asf1A function during the DNA damage response in G2 to allow for proper restoration of chromatin structure at the break site and subsequent recovery from the arrest.
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wytse
authors.initials: W
authors.lastname: Bruinsma
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van den Berg
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Melinda
authors.initials: M
authors.lastname: Aprelia
authors.affiliation: Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands r.medema@nki.nl.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D004789:Enzyme Activation; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; D006657:Histones; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D011494:Protein Kinases; C121377:protein kinase U
keywords: Asf1A; DNA damage; Tlk2; cell cycle; checkpoint recovery