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Expression of  RAD51 , a crucial player in homologous recombination (HR) and DNA double-strand break (DSB) repair, is dysregulated in human tumors, and can contribute to genomic instability and tumor progression. To further understand  RAD51  regulation we functionally characterized a long non-coding (lnc) RNA, dubbed  TODRA  ( T ranscribed in the  O pposite  D irection of   RA    D51 ), transcribed 69bp upstream to  RAD51 , in the opposite direction. We demonstrate that  TODRA  is an expressed transcript and that the  RAD51  promoter region is bidirectional, supporting  TODRA  expression (7-fold higher than RAD51 in this assay, p = 0.003).  TODRA  overexpression in HeLa cells induced expression of  TPIP , a member of the TPTE family which includes PTEN. Similar to PTEN, we found that TPIP co-activates E2F1 induction of  RAD51 . Analysis of E2F1's effect on the bidirectional promoter showed that E2F1 binding to the same site that promotes  RAD51  expression, results in downregulation of  TODRA . Moreover,  TODRA  overexpression induces HR in a RAD51-dependent DSB repair assay, and increases formation of DNA damage-induced RAD51-positive foci. Importantly, gene expression in breast tumors supports our finding that E2F1 oppositely regulates  RAD51  and  TODRA : increased  RAD51  expression, which is associated with an aggressive tumor phenotype (e.g. negative correlation with positive ER (r = -0.22, p = 0.02) and positive PR status (r = -0.27, p<0.001); positive correlation with ki67 status (r = 0.36, p = 0.005) and  HER2  amplification (r = 0.41, p = 0.001)), correlates as expected with lower  TODRA  and higher  E2F1  expression. However, although E2F1 induction resulted in  TPIP  downregulation in cell lines, we find that  TPIP  expression in tumors is not reduced despite higher  E2F1  expression, perhaps contributing to increased  RAD51  expression. Our results identify TPIP as a novel E2F1 co-activator, suggest a similar role for other TPTEs, and indicate that the  TODRA  lncRNA affects RAD51 dysregulation and RAD51-dependent DSB repair in malignancy. Importantly, gene expression in breast tumors supports our finding that E2F1 oppositely regulates RAD51 and TODRA: increased RAD51 expression, which is associated with an aggressive tumor phenotype (e.g. negative correlation with positive ER (r = -0.22, p = 0.02) and positive PR status (r = -0.27, p<0.001); positive correlation with ki67 status (r = 0.36, p = 0.005) and HER2 amplification (r = 0.41, p = 0.001)), correlates as expected with lower TODRA and higher E2F1 expression. However, although E2F1 induction resulted in TPIP downregulation in cell lines, we find that TPIP expression in tumors is not reduced despite higher E2F1 expression, perhaps contributing to increased RAD51 expression. Our results identify TPIP as a novel E2F1 co-activator, suggest a similar role for other TPTEs, and indicate that the TODRA lncRNA affects RAD51 dysregulation and RAD51-dependent DSB repair in malignancy.

TODRA, a lncRNA at the RAD51 Locus, Is Oppositely Regulated to RAD51, and Enhances RAD51-Dependent DSB (Double Strand Break) Repair