RESUMEN
Poly ADP⁃ribose polymerase 1 (PARP1) is an important modification enzyme in cells. Its most well⁃known function is to recruit multiple DNA damage repair effector proteins through its own PARylation, such as XRCC1, to participate in DNA single and double strand damage repair. In addition, PARP1 can also provide favorable conditions for DNA damage repair and maintain genomic stability by promoting replication fork stall and nucleosome depolymerization. In recent years, in addition to the function of DNA damage repair, PARP1 has also been found to play an important role in cell apoptosis, autophagy and inflammatory pathways, which is closely related to the occurrence and development of neurodegenerative diseases. PARP inhibitor (PARPi) is an antitumor drug that targets PARP1 and works together with a homologous recombination (HR) deficient phenotype to produce a synthetic lethality. The drug can trap PARP1 and inhibit its activity. On the one hand, it directly interferes with the DNA damage repair pathway that PARP1 participates in; and on the other hand, it also inhibits the selection of PARP1⁃mediated DNA damage repair pathway and replication fork stall, making the cell genome instable. However, tumor cells are often found to be insensitive to PARPi in clinical treatment. Drug resistance of tumor cells to PARPi is highly correlated with mutations of their own genes, which respectively act on cell HR repair pathway, PARP1 circulation pathway, replication fork stability and active drug efflux, etc. Identifying specific mutation sites in drug⁃resistant tumor cells will provide help for clinical treatment. The purpose of this review is to give a description about the functions of PARP1, and focus on the mechanism of action of PARPi, the mutated genes related to drug resistance and their drug resistance mechanism, therefore to deepen the understanding of PARP1 mediated DNA damage repair pathway in cells, and provide new ideas for future clinical treatment.
RESUMEN
Maintenance of cellular homeostasis and genome integrity is a critical responsibility of DNA double-strand break (DSB) signaling. P53-binding protein 1 (53BP1) plays a critical role in coordinating the DSB repair pathway choice and promotes the non-homologous end-joining (NHEJ)-mediated DSB repair pathway that rejoins DSB ends. New insights have been gained into a basic molecular mechanism that is involved in 53BP1 recruitment to the DNA lesion and how 53BP1 then recruits the DNA break-responsive effectors that promote NHEJ-mediated DSB repair while inhibiting homologous recombination (HR) signaling. This review focuses on the up- and downstream pathways of 53BP1 and how 53BP1 promotes NHEJ-mediated DSB repair, which in turn promotes the sensitivity of poly(ADP-ribose) polymerase inhibitor (PARPi) in BRCA1-deficient cancers and consequently provides an avenue for improving cancer therapy strategies.