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To unveil it, we searched for the mediator bridging PARP1 to ATM pathways by screening 211 human ubiquitin-related proteins. We discovered TRIM44 as a crucial mediator that recruits the MRN complex to damaged chromatin, independent of PARP1 activity. TRIM44 binds PARP1 and regulates the ubiquitination-PARylation balance of PARP1, which facilitates timely recruitment of the MRN complex for DSB repair. Upon exposure to PARPi, TRIM44 shifts its binding from PARP1 to the MRN complex via its ZnF UBP domain. Knockdown of TRIM44 in cells significantly enhances the sensitivity to olaparib and overcomes the resistance to olaparib induced by 53BP1 deficiency. These observations emphasize the central role of TRIM44 in tethering PARP1 to the ATM-mediated repair pathway. Suppression of TRIM44 may enhance PARPi effectiveness and broaden their use even to HR-proficient tumors.<\/jats:p>","DOI":"10.1093\/nar\/gkae756","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T10:05:12Z","timestamp":1724148312000},"page":"11720-11737","source":"Crossref","is-referenced-by-count":5,"title":["PARP1-TRIM44-MRN loop dictates the response to PARP inhibitors"],"prefix":"10.1093","volume":"52","author":[{"given":"Yonghyeon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunwoo","family":"Min","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]},{"name":"Department of Biochemistry, Chungnam National University , Daejeon\u00a0 34134 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seo\u00a0Yun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]},{"name":"Department of Life Science and Multidisciplinary Genome Institute, Hallym University , Chuncheon 24252,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeon-Ji","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yungyeong","family":"Heo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soon\u00a0Sang","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae\u00a0Jun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5237-095X","authenticated-orcid":false,"given":"Ho\u00a0Chul","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Physiology, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hoon","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health San Antonio , TX\u00a0 78229-3000 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4672-8887","authenticated-orcid":false,"given":"Hyeseong","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Ajou University School of Medicine , Suwon\u00a0 16499 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,1]]},"reference":[{"key":"2024102814480670900_B1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/85798","article-title":"DNA double-strand breaks: signaling, repair and the cancer connection","volume":"27","author":"Khanna","year":"2001","journal-title":"Nat. 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