Background Whilst the proto-oncogene PTTG and its binding partner PBF have been shown to be up-regulated in differentiated thyroid cancer, there is a paucity of information regarding their co-expression and specific roles in tumour progression. In particular, PTTG and PBF have both been reported to modulate the tumour suppressor p53, whose activity is impaired in most human cancers. Therefore, the role of PTTG and PBF in thyroid tumorigenesis may involve disruption of p53 pathways that are central to DNA-damage repair (DDR), cell growth and apoptosis. Methods In the present study we investigated the association of PTTG and PBF with p53-related genes in the TCGA thyroid cancer dataset, as well as in a bi-transgenic murine model (Bi-Tg) overexpressing PTTG and PBF specifically in the thyroid gland.Results Characterisation of primary murine Bi-Tg thyrocytes revealed that coexpression of PTTG and PBF caused extensive repression of DDR genes (39/82 genes; P < 0.05). Of these, 31 genes were downregulated >1.5-fold, including genes with key roles in maintaining genomic integrity such as Brca1. Irradiation exposure to increase intracellular p53 further showed significant differences in overall DDR gene expression (n = 82 genes) between irradiated Bi-Tg and wild type thyrocytes (P = 2.4 × 10−4 ) that was greater than either PBF-Tg (P = 1.5 × 10−3 ) or PTTG-Tg thyrocytes (P = NS). By comparison in the TCGA dataset, there were striking correlations with PTTG and PBF in well-characterised p53-related gene panels (P < 0.05; 82–96 genes per panel; n = 322 unmatched TCGA tumour samples). Importantly, nearly half of the significant DDR gene alterations in Bi-Tg thyrocytes were also present in TCGA comparing samples with either low or high PTTG/PBF mRNA levels. Furthermore, the overall survival (P = 0.0002) and disease-free survival (P = 0.02) was poorer for TCGA individuals with high tumoural PTTG/PBF expression (n = 20) than for all other patients (n = 255). Conclusions Altogether our findings provide important insights into the association of p53-related genes with PTTG and PBF in thyroid tumourigenesis.