Cell cycle and apoptosis regulator 2 (CCAR2, formerly known as DBC1) is a
nuclear protein largely involved in DNA damage response, apoptosis, metabolism,
chromatin structure and transcription regulation. Upon DNA lesions, CCAR2 is phosphorylated by the apical
kinases ATM/ATR and this phosphorylation enhances CCAR2 binding to
SIRT1, leading to
SIRT1 inhibition, p53 acetylation and p53-dependent apoptosis. Recently, we found that also the checkpoint
kinase Chk2 and the
proteasome activator REGγ are required for efficient CCAR2-mediated inhibition of
SIRT1 and induction of p53-dependent apoptosis.Here, we report that CCAR2 is required for the repair of heterochromatic DNA lesions, as cells knock-out for CCAR2 retain, at late time-points after genotoxic treatment, abnormal levels of DNA damage-associated nuclear foci, whose timely resolution is reinstated by HP1β depletion. Conversely, repair of
DNA damages in
euchromatin are not affected by CCAR2 absence.We also report that the impairment in heterochromatic DNA repair is caused by defective Chk2 activation, detectable in CCAR2 ablated cells, which finally impacts on the phosphorylation of the Chk2 substrate KAP1 that is required for the induction of
heterochromatin relaxation and DNA repair.These studies further extend and confirm the role of CCAR2 in the DNA damage response and DNA repair and illustrate a new mechanism of Chk2 activity regulation. Moreover, the involvement of CCAR2 in the repair of heterochromatic DNA breaks suggests a new role for this
protein in the maintenance of
chromosomal stability, which is necessary to prevent
cancer formation.