Deacetylated PCBP1 licenses PARP1 activity for DNA damage repair

Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor and one of the initiating enzymes essential for DNA repair. Understanding how to control PARP1 activity is critical for developing strategies to maintain genome stability. Here, we report that the RNA-binding protein poly(rC)-binding protein 1 (PCBP1) interacts with and inhibits PARP1 activity under physiological conditions, and that this inhibition is relieved in the early phase of the DNA damage response. Mechanistically, histone deacetylase SIRT7 mediates the deacetylation of PCBP1 at K314 and K351, disrupting its interaction with the DNA-binding domain of PARP1 and thereby permitting PARP1 activation. Modulating PCBP1 expression or acetylation through gene editing or antagonistic peptides affects the efficiency of DNA damage repair in both cell and murine models. Reduced PCBP1 levels are associated with poor survival in cancer patients following radiotherapy. This regulatory role for PCBP1 in PARP1 activity may form the basis of a therapeutic strategy that combines the inhibition of PCBP1 deacetylation with DNA-damaging agents.