The p53-binding protein 1 (53BP1) is a DNA damage response factor, which is recruited to nuclear structures at the site of DNA damage. DNA double-strand breaks (DSBs) are mutations that are detrimental to cell viability and genome stability, and must be repaired either through homologous recombination (HR) or non-homologous end joining (NHEJ). 53BP1 specifically promotes both NHEJ as well as the inhibition of HR repair, yet the decision making on a molecular level between these two routes not clearly understood. Recently, a focus has been placed on 53BP1 and the breast cancer gene BRCA1, given that BRCA1 is also an important mediator of our DNA damage response, partially by antagonizing 53BP1 dependent NHEJ. The following studies take a closer look at the relationship with 53BP1 and BRCA1.
Zhang et al introduced the hypothesis that a cell cycle dependent BRCA1-UHRF1 cascade regulates the DSB choice of repair. For starters, they used a 53BP1 antibody as a positive control in an experiment that highlighted that UHRF1 ubiquinates RIF1 via co-immunoprecipitation studies. This experiment was performed using prior reports that 53BP1 inhibits BRCA1 and promotes NHEJ through the recruitment of its downstream effector RIF1. Furthermore, they used a 53BP1 antibody to show that RIF1 was entirely abolished in 53BP1-depleted cells, furthering the relationship of the two proteins. Overall, this data as well as additional data in the article provides novel methods by which BRCA1 antagonizes RIF1 in DNA repair. The suggested molecular pathway is such that RIF1 is recruited to DSB sites following interaction with 53BP1. From here, RIF1 blocks IR-induced BRCA1 localization and ultimately promotes NHEJ alongside 53BP1.
Next, Markova et al studied TP53, 53BP1 and apoptosis in lymphocytes from breast cancer patients undergoing radiation therapy using a 53BP1 antibody. In radiation-induced blood samples, levels of 53BP1 were detected after the first dose, and levels of 53BP1 increased during treatment. Correspondingly, termination of radiotherapy resulted in decreased 53BP1 and DNA damaging effects. Moreover, a positive correlation between levels of 53BP1 and stage of cancer being treated was also established. This research points to potential clinical therapies to increase the efficiency of radiotherapy patients to regulate apoptotic cells during treatment.
Last, Obermeier et al took a combined approach to investigate the relationship between 53BP1 and BRCA1 using previously cited research which showed that hereditary heterozygous mutations in DSB repair genes have been associated with increased susceptibility to breast cancer. Their research specifically honed in on PALB2, a breast cancer risk candidate gene associated with additional genetic factors. Using a 53BP1 antibody in immunofluorescence staining showed that there was an accumulation of 53BP1 foci was reported after exposure to radiation therapy. However, in the end the group discovered a loss of 53BP1 accumulation in breast cancer patients, which has potential prognostic value in triple-negative breast cancer patients.
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