The ribonuclease ZC3H12A stabilizes BRCA1 mRNA in DNA damage response.

Abstract

ZC3H12A is an endoribonuclease that destabilizes target transcripts by recognizing stem-loop structures containing a pyrimidine-purine-pyrimidine loop. Here, we identify ZC3H12A as a constitutive stabilizer of BRCA1 mRNA that supports DNA repair capacity. Under basal conditions, depletion of ZC3H12A shortens the half-life of BRCA1 mRNA, reduces its ribosomal loading and lowers BRCA1 protein levels, whereas overexpression has the opposite effect. ZC3H12A binds to the BRCA1 transcript via its PilT N-terminal (PIN) and CCCH-type zinc finger (ZF) domains; enhanced crosslinking and immunoprecipitation (eCLIP) narrows the bound sequence to defined intervals that lie outside the canonical stem-loop element through which ZC3H12A recognizes inflammatory transcripts. Moreover, ionizing radiation induces TBK1-dependent phosphorylation of ZC3H12A at Ser386, accompanied by the export of ZC3H12A from the nucleus and its redistribution to cytoplasmic ribosomes. Phosphorylated ZC3H12A occupies a broader region of BRCA1 transcript without promoting its degradation, thereby further prolonging its half-life and increasing its ribosomal loading. As a result, under genotoxic stress, the supply of BRCA1 increases, thereby supporting RAD51 recruitment and homologous recombination repair. These findings identify ZC3H12A as a post-transcriptional regulator of BRCA1 mRNA and show how Ser386 phosphorylation amplifies a protective function that is already present before damage.