53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone homeostasis maintains genomic integrity

p53-binding protein 1 (53BP1) regulates DNA double-strand break (DSB) repair and maintains genomic integrity. We found that 53BP1 increases the phosphorylation of ATP citrate lyase (ACLY) by direct binding and enhances ACLY activity. This 53BP1-ACLY functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation of the SLBP promoter. This chain of regulatory processes carried out by 53BP1, ACLY, and SLBP is essential for proper 3`-end processing of histone mRNAs and is crucial for both quantitative and qualitative histone homeostasis and the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DSB repair-independent function of 53BP1 in maintaining the genomic stability through the regulatory network with ACLY and SLBP.