Identifying the role of ID3 in DNA repair and maintenance of genome integrity to establish new treatment options for ID3-deficient cancers

(Supported by a grant from the German Research Foundation (DFG), #429192355 to Ali Bakr).
The inhibitor of DNA-binding 3 (ID3) is a transcriptional repressor protein that limits the binding of basic helix-loop-helix (bHLH) transcription factors to DNA. ID3 expression is frequently deregulated in human cancers. We previously reported that pancreatic acinar cell carcinoma (ACC) display a high genomic instability accompanied with loss of ID3 protein in almost 90% of ACCs, and that 70% of them displayed mutational signatures associated with DNA repair defects (Jäkel et al., 2017 Nat. Commun.). Our recently published results (Bakr et al., 2021 NAR) confirm that cellular depletion of ID3 is associated with an impaired DNA damage response and that ID3 promotes homologous recombination (HR). Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.
Based on our published and unpublished preliminary results, we hypothesize that ID3 has the potential to epigenetically affect DNA repair by regulating the changes in the chromatin environment of genomic regions flanking DSBs and/or by affecting the expression of the involved epigenetic factors. We therefore aim to address this and elucidate the possible underlying mechanisms.