GSK3β guides chromosomal repair pathway selection to support BRCA1-independent PARP inhibitor sensitivity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41243967.
- Also identified by DOI 10.1172/JCI197910 and PMC identifier 12618056.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Glycogen synthase kinase-3β (GSK3β) is an established regulator in the DNA double-strand break (DSB) repair pathway. Recent work by Allam et al. revealed a mechanism of DSB repair pathway choice through GSK3β-mediated, site-specific phosphorylation of the tumor suppressor p53 binding protein 1 (53BP1) at threonine 334 (T334). 53BP1 T334 phosphorylation prevented interaction between 53BP1 and its downstream functional partners, PTIP and RIF1, thereby inhibiting 53BP1-directed nonhomologous end joining (NHEJ). Additionally, 53BP1 T334 phosphorylation promoted recruitment of CtIP and RPA32 to DNA damage sites to facilitate homologous recombination (HR). In contrast with loss of 53BP1 function, a 53BP1 T334A phospho-deficient mutant accumulated aberrantly at DSBs, where it impaired end resection and suppressed HR activity. These surprising results suggest that GSK3β may select between NHEJ and HR DNA repair pathways. Additionally, these data support targeting the GSK3β/53BP1 axis to enhance PARP inhibitor efficacy in solid tumors, regardless of BRCA1 status.
Medical subject headings
- BRCA1 Protein
- Poly(ADP-ribose) Polymerase Inhibitors
- DNA End-Joining Repair
- Glycogen Synthase Kinase 3
- DNA Repair