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

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...

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Main Authors: Bakr, Ali (Author) , Hey, Joschka (Author) , Sigismondo, Gianluca (Author) , Liu, Chun-Shan (Author) , Sadik, Ahmed (Author) , Goyal, Ashish (Author) , Cross, Alice (Author) , Iyer, Ramya Lakshmana (Author) , Müller, Patrick (Author) , Trauernicht, Max (Author) , Breuer, Kersten (Author) , Lutsik, Pavlo (Author) , Opitz, Christiane (Author) , Krijgsveld, Jeroen (Author) , Weichenhan, Dieter (Author) , Plass, Christoph (Author) , Popanda, Odilia (Author) , Schmezer, Peter (Author)
Format: Article (Journal)
Language:English
Published: 28 October 2021
In: Nucleic acids research
Year: 2021, Volume: 49, Issue: 20, Pages: 11666-11689
ISSN:1362-4962
DOI:10.1093/nar/gkab964
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/nar/gkab964
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Author Notes:Ali Bakr, Joschka Hey, Gianluca Sigismondo, Chun-Shan Liu, Ahmed Sadik, Ashish Goyal, Alice Cross, Ramya Lakshmana Iyer, Patrick Müller, Max Trauernicht, Kersten Breuer, Pavlo Lutsik, Christiane A Opitz, Jeroen Krijgsveld, Dieter Weichenhan, Christoph Plass, Odilia Popanda, Peter Schmezer
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Summary: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.
Item Description:Gesehen am 27.01.2022
Physical Description:Online Resource
ISSN:1362-4962
DOI:10.1093/nar/gkab964

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