{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:48:51Z","timestamp":1791121731122,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-19-0201-CSM"],"award-info":[{"award-number":["RSG-19-0201-CSM"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RSG-19-0201-CSM"],"award-info":[{"award-number":["RSG-19-0201-CSM"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA258372"],"award-info":[{"award-number":["R01CA258372"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01CA258372"],"award-info":[{"award-number":["R01CA258372"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Patients are treated with DNA damaging chemotherapies which act by inducing DNA damage in rapidly dividing tumor cells. Unfortunately, these tumors frequently develop treatment resistance, underscoring the need to understand resistance mechanisms in order to develop better treatment strategies. DNA damage response (DDR) detects and repairs DNA damage, and the DDR pathway has been shown to contribute to chemoresistance. Another factor known to drive chemoresistance in PDAC is the dense stroma, composed of extracellular matrix proteins secreted by cancer-associated fibroblasts (CAFs). Our recent work identified a CAF-induced resistance mechanism involving N-myc downstream regulated gene 1 (NDRG1). CAF-induced signaling resulted in the phosphorylation of NDRG1 and NDRG1-dependent DNA repair and protection from chemotherapies. Loss of NDRG1 resulted in increased chemotherapy-induced DNA damage and decreased replication fork speed and recovery. Methods: To gain insight into the molecular mechanism of NDRG1-mediated DNA repair and replication, we performed a BioID screen to identify binding partners of NDRG1. We further assessed the mechanistic roles of the identified interaction partners on DNA repair using DNA replication and repair assays such as the Comet assay and DNA fiber assays. Results: Our BioID screen identified meiotic recombination 11 (MRE11) protein, a nuclease involved in DDR, as a putative NDRG1 interacting protein. Interaction between MRE11 and NDRG1 was enriched during the late S\/early G2 cell cycle phases and under replication stress. However, this interaction is likely indirect as the interaction only occurred in a cellular context and not with in vitro purified proteins. Blocking NDRG1 phosphorylation or blocking MRE11 exonuclease activity both resulted in protection of newly synthesized DNA at stalled replication forks. In NDRG1 knockout cells, blocking MRE11 led to decreased protection of nascent DNA, suggesting that NDRG1 and MRE11 may be acting in the same pathway and that NDRG1 is required for MRE11\u2019s activity at stalled forks. Conclusions: In summary, our work has uncovered a protein complex between NDRG1 and MRE11 that may play a key role in chemoresistance due to its role in the processing of stalled replication forks.<\/jats:p>","DOI":"10.3390\/cancers18081303","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T14:53:23Z","timestamp":1776696803000},"page":"1303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interaction of NDRG1 and MRE11 Modulates DNA Replication and Repair"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0781-611X","authenticated-orcid":false,"given":"Hanna M.","family":"Doh","sequence":"first","affiliation":[{"name":"Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"},{"name":"BIDMC Cancer Center, BIDMC Cancer Research Institute, Boston, MA 02215, USA"},{"name":"Biological and Biomedical Science PhD Program, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kozlova","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"},{"name":"BIDMC Cancer Center, BIDMC Cancer Research Institute, Boston, MA 02215, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5693-7359","authenticated-orcid":false,"given":"Zhipeng A.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Desai Sethi Urology Institute & Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwan","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6873-7824","authenticated-orcid":false,"given":"Philip A.","family":"Cole","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-9002","authenticated-orcid":false,"given":"Taru","family":"Muranen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"},{"name":"BIDMC Cancer Center, BIDMC Cancer Research Institute, Boston, MA 02215, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Medicine, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/S0140-6736(25)00261-2","article-title":"Pancreatic cancer","volume":"405","author":"Stoop","year":"2025","journal-title":"Lancet"},{"key":"ref_2","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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