Research Paper Volume 11, Issue 23 pp 11268—11313

Figure 10. RXFP3 in DNA damage response and repair. (A) With DNA damage in the form of a double strand break (DSB), the cell has several mechanisms to respond and thus repair itself. The damage is recognized by the MRE11-RAD50-NBS1 complex (MRN complex), which recruits and activates ATM (Ataxia Telangiectasia Mutated), which is autophosphorylated. ATM, in turn phosphorylates multiple damage-associated proteins. H2AX (a variant of the histone H2A family) phosphorylation (generating γ-H2AX) allows for the recruitment of MDC1 (Mediator of Damage Checkpoint protein 1), also a phosphorylation substrate of ATM. Phosphorylated MDC1 serves as a scaffold for the recruitment of other proteins required for the activation of BRCA1 by ATM, thus promoting cell cycle arrest and DNA repair. BRCA1, in turn, then interacts with multiple proteins, i.e. p53, RAD50, RAD51, ATM, NSB1 and BRCA2, to modulate DNA repair, transcription, and the cell cycle. Phosphorylation of BRCA1 by ATM activates DNA repair through homologous recombination, in cooperation with BRCA2 and RAD51. Additionally, BRCA1 recruits the MRN-complex to the sites of DNA damage. ATM furthermore phosphorylates the aging keystone GIT2 promotes the repair of DNA damage via the stabilization of repair factor BRCA1, in the repair complex. GIT2 then allows the formation of a nuclear DSB focus dependent on H2AX, ATM, and MRE11. Also GIT2 is a strong interactor of the cell cycle checkpoint protein p53 and PARP1. PARPs play a pivotal role in DNA damage detection and repair, by the formation of ADP-ribose ribosylation complexes, allowing the recruitment of DDR proteins to the damaged DNA. After the DNA has been repaired, γ-H2AX is dephosphorylated by PP2A, a phosphatase. (B) Cells exploit two major DSB repair pathways, i) ATM-dependent homologous recombination (HR), and ii) PRKDC-mediated Non-homologous end joining (NHEJ). In the absence of a functional ATM, it seems cells are able to rely on functional PRKDC signaling for their survival, thus using the NHEJ pathway as a backup pathway for DSB repair [191].