Fig. 7

CCDC6 is a functional regulator of the PP4c Phosphatase activity. A The ATM kinase phosphorylates histone H2AX at S129 in the presence of DNA Double Strand Breaks (DSBs) to initiate homologous recombination DNA repair. The protein phosphatase PP4c, which is complexed with the PP43α/β regulatory subunits, dephosphorylates histone H2AX at the completion of the repair process, allowing the cell cycle to continue. The ATM kinase also phosphorylates the CCDC6 protein at residue Threonine 434 in response to DNA damage, which adversely controls the phosphatase function of the PP4c holoenzyme via the F423xxP426 motif, retaining the phosphorylated histone H2AX activity. B The phosphorylation of Threonine 427, which flanks by the CCDC6-PP4c interaction motif, inhibits CCDC6 from binding to PP4, allowing its phosphatase activity on γH2AX to be released, resulting in HR deficiency and, as a result, PARPi sensitivity. C This effect also occurs when PP4c is released in response to the physical or functional loss of CCDC6, which might be caused by a variety of processes (e.g., CCDC6 truncation after gene fusion, somatic mutations, or accelerated degradation due to post translational alterations, etc.)