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. image During a DNA damage‐induced arrest in G2, Tlk2 controls the restoration of chromatin structure through the histone chaperone Asf1A. Failure to do so leads to reduced transcription of pro‐mitotic genes and subsequent loss of the competence to recover from a DNA damage‐induced arrest. Tlk2 is essential for checkpoint recovery. Tlk2 controls Asf1A‐dependent restoration of chromatin structure. Tlk2/Asf1A pathway deficiency leads to a loss of recovery competence.