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RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA
Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report...
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Published in: | Molecular cell 2022-11, Vol.82 (21), p.4001-4017.e7 |
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creator | Kaminski, Nicole Wondisford, Anne R. Kwon, Youngho Lynskey, Michelle Lee Bhargava, Ragini Barroso-González, Jonathan García-Expósito, Laura He, Boxue Xu, Meng Mellacheruvu, Dattatreya Watkins, Simon C. Modesti, Mauro Miller, Kyle M. Nesvizhskii, Alexey I. Zhang, Huaiying Sung, Patrick O’Sullivan, Roderick J. |
description | Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R-loop HR intermediates. We also show that RAD51AP1 binds to and might stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a role for RAD51AP1-mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions (TRCs) during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA.
[Display omitted]
•RAD51AP1 and TERRA interact and stimulate the formation of D and R loops•TERRA R-loops generated by RAD51AP1 regulate repressive chromatin at telomeres•RAD51AP1 protects telomeric regions from transcription-replication collisions
Kaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR. |
doi_str_mv | 10.1016/j.molcel.2022.09.025 |
format | article |
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[Display omitted]
•RAD51AP1 and TERRA interact and stimulate the formation of D and R loops•TERRA R-loops generated by RAD51AP1 regulate repressive chromatin at telomeres•RAD51AP1 protects telomeric regions from transcription-replication collisions
Kaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2022.09.025</identifier><identifier>PMID: 36265488</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ALT ; cancer ; chromatin ; Chromatin - genetics ; Homeostasis ; homology-directed repair ; Life Sciences ; Proteomics ; RAD51AP1 ; RNA, Long Noncoding - genetics ; telomere ; Telomere - genetics ; Telomere - metabolism ; Telomere Homeostasis ; TERRA ; transcription</subject><ispartof>Molecular cell, 2022-11, Vol.82 (21), p.4001-4017.e7</ispartof><rights>2022 The Author(s)</rights><rights>Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-6b6cb2b439b61a4619c8fdd40458badb7260a1e6c4cbb4c1c7cc35812b9c29143</citedby><cites>FETCH-LOGICAL-c500t-6b6cb2b439b61a4619c8fdd40458badb7260a1e6c4cbb4c1c7cc35812b9c29143</cites><orcidid>0000-0002-0289-0911 ; 0000-0002-4964-331X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36265488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-03825785$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Kaminski, Nicole</creatorcontrib><creatorcontrib>Wondisford, Anne R.</creatorcontrib><creatorcontrib>Kwon, Youngho</creatorcontrib><creatorcontrib>Lynskey, Michelle Lee</creatorcontrib><creatorcontrib>Bhargava, Ragini</creatorcontrib><creatorcontrib>Barroso-González, Jonathan</creatorcontrib><creatorcontrib>García-Expósito, Laura</creatorcontrib><creatorcontrib>He, Boxue</creatorcontrib><creatorcontrib>Xu, Meng</creatorcontrib><creatorcontrib>Mellacheruvu, Dattatreya</creatorcontrib><creatorcontrib>Watkins, Simon C.</creatorcontrib><creatorcontrib>Modesti, Mauro</creatorcontrib><creatorcontrib>Miller, Kyle M.</creatorcontrib><creatorcontrib>Nesvizhskii, Alexey I.</creatorcontrib><creatorcontrib>Zhang, Huaiying</creatorcontrib><creatorcontrib>Sung, Patrick</creatorcontrib><creatorcontrib>O’Sullivan, Roderick J.</creatorcontrib><title>RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R-loop HR intermediates. We also show that RAD51AP1 binds to and might stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a role for RAD51AP1-mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions (TRCs) during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA.
[Display omitted]
•RAD51AP1 and TERRA interact and stimulate the formation of D and R loops•TERRA R-loops generated by RAD51AP1 regulate repressive chromatin at telomeres•RAD51AP1 protects telomeric regions from transcription-replication collisions
Kaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR.</description><subject>ALT</subject><subject>cancer</subject><subject>chromatin</subject><subject>Chromatin - genetics</subject><subject>Homeostasis</subject><subject>homology-directed repair</subject><subject>Life Sciences</subject><subject>Proteomics</subject><subject>RAD51AP1</subject><subject>RNA, Long Noncoding - genetics</subject><subject>telomere</subject><subject>Telomere - genetics</subject><subject>Telomere - metabolism</subject><subject>Telomere Homeostasis</subject><subject>TERRA</subject><subject>transcription</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kUtv1DAUhS0EoqXwDxDKkkWT2o7txBukqC0M1UitRsPasp07E4-SuNjJSPx7XGUojwWra8nnnPv4EHpPcEEwEVeHYvC9hb6gmNICywJT_gKdEyyrnBHBXp7etBL8DL2J8YAxYbyWr9FZKajgrK7P0d2mueGkeSBZgP3c6wli1qy3-epmk01d8PO-y2yqg57cmLcugJ2gzTo_gI-Tji5mfpdtbzeb5i16tdN9hHeneoG-fb7dXq_y9f2Xr9fNOrcc4ykXRlhDDSulEUQzQaStd23LcJrN6NZUVGBNQFhmjWGW2MrakteEGmmpJKy8QJ-W3MfZDNBaGKege_UY3KDDD-W1U3__jK5Te39UsiKl5DQFXC4B3T-2VbNWbowQBoXLmvKq5keS5B9P_YL_PkOc1OBiOnyvR_BzVLRKJ2ZlyXiSskVqg48xwO45nmD1RE0d1EJNPVFTWKpELdk-_LnRs-kXpt8rQ7rr0UFQ0ToYLSxAVOvd_zv8BKJ7qbY</recordid><startdate>20221103</startdate><enddate>20221103</enddate><creator>Kaminski, Nicole</creator><creator>Wondisford, Anne R.</creator><creator>Kwon, Youngho</creator><creator>Lynskey, Michelle Lee</creator><creator>Bhargava, Ragini</creator><creator>Barroso-González, Jonathan</creator><creator>García-Expósito, Laura</creator><creator>He, Boxue</creator><creator>Xu, Meng</creator><creator>Mellacheruvu, Dattatreya</creator><creator>Watkins, Simon C.</creator><creator>Modesti, Mauro</creator><creator>Miller, Kyle M.</creator><creator>Nesvizhskii, Alexey I.</creator><creator>Zhang, Huaiying</creator><creator>Sung, Patrick</creator><creator>O’Sullivan, Roderick J.</creator><general>Elsevier Inc</general><general>Cell Press</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0289-0911</orcidid><orcidid>https://orcid.org/0000-0002-4964-331X</orcidid></search><sort><creationdate>20221103</creationdate><title>RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA</title><author>Kaminski, Nicole ; Wondisford, Anne R. ; Kwon, Youngho ; Lynskey, Michelle Lee ; Bhargava, Ragini ; Barroso-González, Jonathan ; García-Expósito, Laura ; He, Boxue ; Xu, Meng ; Mellacheruvu, Dattatreya ; Watkins, Simon C. ; Modesti, Mauro ; Miller, Kyle M. ; Nesvizhskii, Alexey I. ; Zhang, Huaiying ; Sung, Patrick ; O’Sullivan, Roderick J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-6b6cb2b439b61a4619c8fdd40458badb7260a1e6c4cbb4c1c7cc35812b9c29143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>ALT</topic><topic>cancer</topic><topic>chromatin</topic><topic>Chromatin - genetics</topic><topic>Homeostasis</topic><topic>homology-directed repair</topic><topic>Life Sciences</topic><topic>Proteomics</topic><topic>RAD51AP1</topic><topic>RNA, Long Noncoding - genetics</topic><topic>telomere</topic><topic>Telomere - genetics</topic><topic>Telomere - metabolism</topic><topic>Telomere Homeostasis</topic><topic>TERRA</topic><topic>transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kaminski, Nicole</creatorcontrib><creatorcontrib>Wondisford, Anne R.</creatorcontrib><creatorcontrib>Kwon, Youngho</creatorcontrib><creatorcontrib>Lynskey, Michelle Lee</creatorcontrib><creatorcontrib>Bhargava, Ragini</creatorcontrib><creatorcontrib>Barroso-González, Jonathan</creatorcontrib><creatorcontrib>García-Expósito, Laura</creatorcontrib><creatorcontrib>He, Boxue</creatorcontrib><creatorcontrib>Xu, Meng</creatorcontrib><creatorcontrib>Mellacheruvu, Dattatreya</creatorcontrib><creatorcontrib>Watkins, Simon C.</creatorcontrib><creatorcontrib>Modesti, Mauro</creatorcontrib><creatorcontrib>Miller, Kyle M.</creatorcontrib><creatorcontrib>Nesvizhskii, Alexey I.</creatorcontrib><creatorcontrib>Zhang, Huaiying</creatorcontrib><creatorcontrib>Sung, Patrick</creatorcontrib><creatorcontrib>O’Sullivan, Roderick J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kaminski, Nicole</au><au>Wondisford, Anne R.</au><au>Kwon, Youngho</au><au>Lynskey, Michelle Lee</au><au>Bhargava, Ragini</au><au>Barroso-González, Jonathan</au><au>García-Expósito, Laura</au><au>He, Boxue</au><au>Xu, Meng</au><au>Mellacheruvu, Dattatreya</au><au>Watkins, Simon C.</au><au>Modesti, Mauro</au><au>Miller, Kyle M.</au><au>Nesvizhskii, Alexey I.</au><au>Zhang, Huaiying</au><au>Sung, Patrick</au><au>O’Sullivan, Roderick J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2022-11-03</date><risdate>2022</risdate><volume>82</volume><issue>21</issue><spage>4001</spage><epage>4017.e7</epage><pages>4001-4017.e7</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Alternative lengthening of telomeres (ALT) is a homology-directed repair (HDR) mechanism of telomere elongation that controls proliferation in subsets of aggressive cancer. Recent studies have revealed that telomere repeat-containing RNA (TERRA) promotes ALT-associated HDR (ALT-HDR). Here, we report that RAD51AP1, a crucial ALT factor, interacts with TERRA and utilizes it to generate D- and R-loop HR intermediates. We also show that RAD51AP1 binds to and might stabilize TERRA-containing R-loops as RAD51AP1 depletion reduces R-loop formation at telomere DNA breaks. Proteomic analyses uncover a role for RAD51AP1-mediated TERRA R-loop homeostasis in a mechanism of chromatin-directed suppression of TERRA and prevention of transcription-replication collisions (TRCs) during ALT-HDR. Intriguingly, we find that both TERRA binding and this non-canonical function of RAD51AP1 require its intrinsic SUMO-SIM regulatory axis. These findings provide insights into the multi-contextual functions of RAD51AP1 within the ALT mechanism and regulation of TERRA.
[Display omitted]
•RAD51AP1 and TERRA interact and stimulate the formation of D and R loops•TERRA R-loops generated by RAD51AP1 regulate repressive chromatin at telomeres•RAD51AP1 protects telomeric regions from transcription-replication collisions
Kaminski et al. show the cooperative roles of RAD51AP1 and TERRA in generating HR intermediates during ALT-HDR. Proteomic analyses uncover that RAD51AP1 binding of R-loops might serve to maintain chromatin that suppresses TERRA and prevents transcription-replication collisions (TRCs) during ALT-HDR.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>36265488</pmid><doi>10.1016/j.molcel.2022.09.025</doi><tpages>-932</tpages><orcidid>https://orcid.org/0000-0002-0289-0911</orcidid><orcidid>https://orcid.org/0000-0002-4964-331X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | ALT cancer chromatin Chromatin - genetics Homeostasis homology-directed repair Life Sciences Proteomics RAD51AP1 RNA, Long Noncoding - genetics telomere Telomere - genetics Telomere - metabolism Telomere Homeostasis TERRA transcription |
title | RAD51AP1 regulates ALT-HDR through chromatin-directed homeostasis of TERRA |
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