Loading…
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...
Saved in:
| Published in: | Nucleic acids research 2021-11, Vol.49 (20), p.11666-11689 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23 |
| container_end_page | 11689 |
| container_issue | 20 |
| container_start_page | 11666 |
| container_title | Nucleic acids research |
| container_volume | 49 |
| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1093/nar/gkab964 |
| format | article |
| fullrecord | <record><control><sourceid>oup_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8599806</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/nar/gkab964</oup_id><sourcerecordid>10.1093/nar/gkab964</sourcerecordid><originalsourceid>FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23</originalsourceid><addsrcrecordid>eNp9kUtLAzEUhYMoWqsr95KVGxm9ecxMZiNIfRUERXQ9JGmmjc4kQzIt9F_4k51aLerC1YF7zv0ul4PQEYEzAgU7dzKcT9-kKjK-hQaEZTThRUa30QAYpAkBLvbQfoyvAISTlO-iPcZzInJOB-h9fMVwG3zjOxPxrNfaT_084mC0b5R1srPe4YWV2HmXdEG6qINtV1NZY-km-O-sMXomnY1N_LRtF3HtY8Tau8qEiKNx0XZ2Ybsl7jx-vHx6xNbNrLIrwAHaqWQdzeGXDtHLzfXz6C65f7gdjy7vE80J7RLBJEAx4boCI8FQlRVKaCkpM4qSHCClQFJBFU0rUeUmVczkJuNGixRAUzZEF2tuO1eNmWjj-j_qsg22kWFZemnL346zs3LqF6VIi0JA1gNO1wAd-u-CqTa7BMpVMWVfTPlVTJ8-_nluk_1uog-crAN-3v5L-gDB8Z1-</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition</title><source>PubMed Central（OA）</source><source>Oxford Journals Online</source><creator>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</creator><creatorcontrib>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</creatorcontrib><description>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.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab964</identifier><identifier>PMID: 34718742</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>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</subject><ispartof>Nucleic acids research, 2021-11, Vol.49 (20), p.11666-11689</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23</citedby><cites>FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23</cites><orcidid>0000-0002-6111-0591</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599806/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599806/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,1591,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34718742$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bakr, Ali</creatorcontrib><creatorcontrib>Hey, Joschka</creatorcontrib><creatorcontrib>Sigismondo, Gianluca</creatorcontrib><creatorcontrib>Liu, Chun-Shan</creatorcontrib><creatorcontrib>Sadik, Ahmed</creatorcontrib><creatorcontrib>Goyal, Ashish</creatorcontrib><creatorcontrib>Cross, Alice</creatorcontrib><creatorcontrib>Iyer, Ramya Lakshmana</creatorcontrib><creatorcontrib>Müller, Patrick</creatorcontrib><creatorcontrib>Trauernicht, Max</creatorcontrib><creatorcontrib>Breuer, Kersten</creatorcontrib><creatorcontrib>Lutsik, Pavlo</creatorcontrib><creatorcontrib>Opitz, Christiane A</creatorcontrib><creatorcontrib>Krijgsveld, Jeroen</creatorcontrib><creatorcontrib>Weichenhan, Dieter</creatorcontrib><creatorcontrib>Plass, Christoph</creatorcontrib><creatorcontrib>Popanda, Odilia</creatorcontrib><creatorcontrib>Schmezer, Peter</creatorcontrib><title>ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>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.</description><subject>Cell Line, Tumor</subject><subject>DNA Breaks, Double-Stranded</subject><subject>Drug Resistance, Neoplasm</subject><subject>E2F1 Transcription Factor - metabolism</subject><subject>Genome Integrity, Repair and</subject><subject>HEK293 Cells</subject><subject>Homologous Recombination</subject><subject>Humans</subject><subject>Inhibitor of Differentiation Proteins - chemistry</subject><subject>Inhibitor of Differentiation Proteins - metabolism</subject><subject>Male</subject><subject>Neoplasm Proteins - chemistry</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - toxicity</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Rad51 Recombinase - metabolism</subject><subject>RecQ Helicases - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kUtLAzEUhYMoWqsr95KVGxm9ecxMZiNIfRUERXQ9JGmmjc4kQzIt9F_4k51aLerC1YF7zv0ul4PQEYEzAgU7dzKcT9-kKjK-hQaEZTThRUa30QAYpAkBLvbQfoyvAISTlO-iPcZzInJOB-h9fMVwG3zjOxPxrNfaT_084mC0b5R1srPe4YWV2HmXdEG6qINtV1NZY-km-O-sMXomnY1N_LRtF3HtY8Tau8qEiKNx0XZ2Ybsl7jx-vHx6xNbNrLIrwAHaqWQdzeGXDtHLzfXz6C65f7gdjy7vE80J7RLBJEAx4boCI8FQlRVKaCkpM4qSHCClQFJBFU0rUeUmVczkJuNGixRAUzZEF2tuO1eNmWjj-j_qsg22kWFZemnL346zs3LqF6VIi0JA1gNO1wAd-u-CqTa7BMpVMWVfTPlVTJ8-_nluk_1uog-crAN-3v5L-gDB8Z1-</recordid><startdate>20211118</startdate><enddate>20211118</enddate><creator>Bakr, Ali</creator><creator>Hey, Joschka</creator><creator>Sigismondo, Gianluca</creator><creator>Liu, Chun-Shan</creator><creator>Sadik, Ahmed</creator><creator>Goyal, Ashish</creator><creator>Cross, Alice</creator><creator>Iyer, Ramya Lakshmana</creator><creator>Müller, Patrick</creator><creator>Trauernicht, Max</creator><creator>Breuer, Kersten</creator><creator>Lutsik, Pavlo</creator><creator>Opitz, Christiane A</creator><creator>Krijgsveld, Jeroen</creator><creator>Weichenhan, Dieter</creator><creator>Plass, Christoph</creator><creator>Popanda, Odilia</creator><creator>Schmezer, Peter</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6111-0591</orcidid></search><sort><creationdate>20211118</creationdate><title>ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Cell Line, Tumor</topic><topic>DNA Breaks, Double-Stranded</topic><topic>Drug Resistance, Neoplasm</topic><topic>E2F1 Transcription Factor - metabolism</topic><topic>Genome Integrity, Repair and</topic><topic>HEK293 Cells</topic><topic>Homologous Recombination</topic><topic>Humans</topic><topic>Inhibitor of Differentiation Proteins - chemistry</topic><topic>Inhibitor of Differentiation Proteins - metabolism</topic><topic>Male</topic><topic>Neoplasm Proteins - chemistry</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - toxicity</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Rad51 Recombinase - metabolism</topic><topic>RecQ Helicases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bakr, Ali</creatorcontrib><creatorcontrib>Hey, Joschka</creatorcontrib><creatorcontrib>Sigismondo, Gianluca</creatorcontrib><creatorcontrib>Liu, Chun-Shan</creatorcontrib><creatorcontrib>Sadik, Ahmed</creatorcontrib><creatorcontrib>Goyal, Ashish</creatorcontrib><creatorcontrib>Cross, Alice</creatorcontrib><creatorcontrib>Iyer, Ramya Lakshmana</creatorcontrib><creatorcontrib>Müller, Patrick</creatorcontrib><creatorcontrib>Trauernicht, Max</creatorcontrib><creatorcontrib>Breuer, Kersten</creatorcontrib><creatorcontrib>Lutsik, Pavlo</creatorcontrib><creatorcontrib>Opitz, Christiane A</creatorcontrib><creatorcontrib>Krijgsveld, Jeroen</creatorcontrib><creatorcontrib>Weichenhan, Dieter</creatorcontrib><creatorcontrib>Plass, Christoph</creatorcontrib><creatorcontrib>Popanda, Odilia</creatorcontrib><creatorcontrib>Schmezer, Peter</creatorcontrib><collection>Open Access: Oxford University Press Open Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bakr, Ali</au><au>Hey, Joschka</au><au>Sigismondo, Gianluca</au><au>Liu, Chun-Shan</au><au>Sadik, Ahmed</au><au>Goyal, Ashish</au><au>Cross, Alice</au><au>Iyer, Ramya Lakshmana</au><au>Müller, Patrick</au><au>Trauernicht, Max</au><au>Breuer, Kersten</au><au>Lutsik, Pavlo</au><au>Opitz, Christiane A</au><au>Krijgsveld, Jeroen</au><au>Weichenhan, Dieter</au><au>Plass, Christoph</au><au>Popanda, Odilia</au><au>Schmezer, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2021-11-18</date><risdate>2021</risdate><volume>49</volume><issue>20</issue><spage>11666</spage><epage>11689</epage><pages>11666-11689</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><notes>The authors wish it to be known that, in their opinion, the second and third authors should be regarded as Joint Second Authors.</notes><abstract>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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>34718742</pmid><doi>10.1093/nar/gkab964</doi><tpages>24</tpages><orcidid>https://orcid.org/0000-0002-6111-0591</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0305-1048 |
| ispartof | Nucleic acids research, 2021-11, Vol.49 (20), p.11666-11689 |
| issn | 0305-1048 1362-4962 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8599806 |
| source | PubMed Central（OA）; Oxford Journals Online |
| 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 |
| title | ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T09%3A24%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-oup_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=ID3%20promotes%20homologous%20recombination%20via%20non-transcriptional%20and%20transcriptional%20mechanisms%20and%20its%20loss%20confers%20sensitivity%20to%20PARP%20inhibition&rft.jtitle=Nucleic%20acids%20research&rft.au=Bakr,%20Ali&rft.date=2021-11-18&rft.volume=49&rft.issue=20&rft.spage=11666&rft.epage=11689&rft.pages=11666-11689&rft.issn=0305-1048&rft.eissn=1362-4962&rft_id=info:doi/10.1093/nar/gkab964&rft_dat=%3Coup_pubme%3E10.1093/nar/gkab964%3C/oup_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c412t-83a009d4cf0ea0e2b69b8caa23eb217005201582b25f8f7e5b3e7e64ec8500c23%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_id=info:pmid/34718742&rft_oup_id=10.1093/nar/gkab964&rfr_iscdi=true |