Acetylation of 53BP1 dictates the DNA double strand break repair pathway

Abstract

P53-binding protein 1 (53BP1) plays critical roles in DNA double strand break (DSB) repair by promoting non-homologous end joining (NHEJ), and loss of 53BP1 abolishes PARPi sensitivity in BRCA1-deficient cells by restoring homologous recombination (HR). 53BP1 is one of the proteins initially recruited to sites of DSBs via recognition of H4K20me2 through the Tudor-UDR domain and H2AK15ub through the UDR motif. Although extensive studies have been conducted, it remains unclear how the post-translational modification of 53BP1 affects DSB repair pathway choice. Here, we identified 53BP1 as an acetylated protein and determined that acetylation of 53BP1 inhibit NHEJ and promote HR by negatively regulating 53BP1 recruitment to DSBs. Mechanistically, CBP-mediated acetylation of K1626/1628 in the UDR motif disrupted the interaction between 53BP1 and nucleosomes, subsequently blocking the recruitment of 53BP1 and its downstream factors PTIP and RIF1 to DSBs. Hyperacetylation of 53BP1, similar to depletion of 53BP1, restored PARPi resistance in BRCA1-deficient cells. Interestingly, 53BP1 acetylation was tightly regulated by HDAC2 to maintain balance between the HR and NHEJ pathways. Together, our results demonstrate that the acetylation status of 53BP1 plays a key role in its recruitment to DSBs and reveal how specific 53BP1 modification modulates the choice of DNA repair pathway.

How cells ensure correct repair of DNA double-strand breaks

“…Just as JMJD2A and L3MBTL1 compete with 53BP1 for H4K20Me 2 binding, the E3 ubiquitin ligases RNF169 and RAD18 also compete with 53BP1 for binding to H2AK15ub (53,54). The ability of 53BP1 to bind to H2AK15ub is also limited by phosphorylation or acetylation of key residues within the ubiquitin-dependent recruitment region (13,55,56). In addition to its recruitment, the stability of 53BP1 is also regulated by proteasome-mediated degradation dependent on the E2 enzyme, UBCH7 (57).…”

Toward understanding genomic instability, mitochondrial dysfunction and aging

“…Thus, human premature aging disorders are strongly associated with defects in DSBR, BER, and NER . Furthermore, repair of DNA damage is an energy demanding process and it is becoming increasingly evident that DNA damage and persistent DDR‐linked cellular stress leads to mitochondrial dysfunction and metabolic defects . The following paragraphs discuss the molecular mechanisms underlying this signaling and how it relates to cellular bioenergetics/energy homeostasis and the cellular abundance of ATP and NAD + .…”

“…Thus, human premature aging disorders are strongly associated with defects in DSBR, BER, and NER [14]. Furthermore, repair of DNA damage is an energy demanding process [15][16][17][18][19][20] and it is becoming increasingly evident that DNA damage and persistent DDR-linked cellular stress leads to mitochondrial dysfunction and metabolic defects [21].…”

Quantitatively profiling acetylome of DNA repair proteins in early DNA damage

“…Increasing studies have revealed that acetylation within the domain region were capable of regulating the function of proteins (19,20). For instance, acetylation of K1626 and K1628 in the Tudor-UDR domain of 53BP1 was dynamic regulated by CBP and KDAC2, which was associated with 53BP1 interaction with nucleosomes and the choice of DNA repair pathway (21). Hence, via analyzing the regions of these acetylation sites on the 50 repair protein, 9 acetylated or deacetylated Kac sites were observed to locate in the function domains of 7 repair proteins.…”