ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition

Abstract The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we de...

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Bibliographic Details
Published in:Nucleic acids research 2021-11, Vol.49 (20), p.11666-11689
Main Authors: Bakr, Ali, Hey, Joschka, Sigismondo, Gianluca, Liu, Chun-Shan, Sadik, Ahmed, Goyal, Ashish, Cross, Alice, Iyer, Ramya Lakshmana, Müller, Patrick, Trauernicht, Max, Breuer, Kersten, Lutsik, Pavlo, Opitz, Christiane A, Krijgsveld, Jeroen, Weichenhan, Dieter, Plass, Christoph, Popanda, Odilia, Schmezer, Peter
Format: Article
Language:English
Subjects:
Cell Line, Tumor
DNA Breaks, Double-Stranded
Drug Resistance, Neoplasm
E2F1 Transcription Factor - metabolism
Genome Integrity, Repair and
HEK293 Cells
Homologous Recombination
Humans
Inhibitor of Differentiation Proteins - chemistry
Inhibitor of Differentiation Proteins - metabolism
Male
Neoplasm Proteins - chemistry
Neoplasm Proteins - metabolism
Poly(ADP-ribose) Polymerase Inhibitors - toxicity
Poly(ADP-ribose) Polymerases - metabolism
Prostatic Neoplasms - genetics
Rad51 Recombinase - metabolism
RecQ Helicases - metabolism
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Summary:Abstract The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. 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. Graphical Abstract Graphical Abstract Dual role of ID3 in promoting homologous recombination.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkab964