ID3 Promotes Homologous Recombination via Non-transcriptional and Transcriptional Mechanisms and its loss confers Sensitivity to PARP

The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with the DNA. ID3 expression is frequently deregulated in human cancers and its loss was shown to impact DNA repair. To understand the molecular mechanisms by which ID3 regulates DNA repair, proteomic and transcriptomic approaches following DNA damage induction were performed in wild-type and ID3-depleted cells. Results show that ID3 promotes DNA double-strand break repair, particularly homologous recombination (HR). Mechanistically, two main pathways were identified through which ID3 contributes to HR, (1) via protein interaction with RAD50 and RECQL, and (2) as a transcriptional regulator. In the latter case, ID3 is required for the expression of specific HR genes in response to ionizing radiation. We conclude that loss of ID3 leads to HR deficiency which subsequently confers sensitivity to PARP inhibition, thus offering new therapeutic options to ID3 deficient cancers.