{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:38:57Z","timestamp":1790224737245,"version":"4.1.0"},"reference-count":119,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"35","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,8,29]]},"abstract":"<jats:p>Replication stress (RS) poses a threat to genome stability and drives genomic rearrangements. The homologous recombination (HR) pathway repairs stalled replication forks (RFs) and prevents such instability. Through an E3 ubiquitin ligase screen aimed at identifying regulators of RAD51, we identified macrophage erythroblast attacher (MAEA), a core component of C-terminal to Lish (CTLH) E3 ubiquitin ligase complex, as a regulator of the HR pathway. Loss of MAEA impairs RAD51 recruitment at stalled RFs, leading to increased sensitivity to RS-inducing agents and excessive degradation of nascent DNA strands. Mechanistically, MAEA associates with and mediates the ubiquitylation of Ku80, enabling its removal from RF ends and facilitating the loading of RAD51. Notably, MAEA deficiency is associated with a developmental disorder involving microcephaly, craniofacial abnormalities, ocular defects, and heart malformations. Functional assays show that disease-linked MAEA variants (R34C, E349G, Y394D, and M396R) are defective in RS response. These findings establish MAEA as an essential factor in RF protection and genome integrity.<\/jats:p>","DOI":"10.1126\/sciadv.adv0381","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T17:58:38Z","timestamp":1756490318000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Pathogenic variants in MAEA disrupt DNA replication fork stability and are associated with developmental abnormalities in humans"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2255-5951","authenticated-orcid":true,"given":"Elham","family":"Zeinali","sequence":"first","affiliation":[{"name":"Department of Oncology, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-9403","authenticated-orcid":true,"given":"Fatemeh","family":"Mashayekhi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1627-8467","authenticated-orcid":true,"given":"Rabih Abou","family":"Farraj","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9726-0787","authenticated-orcid":true,"given":"Talah","family":"Hasanni","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Caron","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Medical Biochemistry and Pathology, CHU de Qu\u00e9bec Research Centre (Oncology Division, H\u00f4pital Enfant-Jesus) and Laval University Cancer Research Center, Qu\u00e9bec City, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Coulombe","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Medical Biochemistry and Pathology, CHU de Qu\u00e9bec Research Centre (Oncology Division, H\u00f4pital Enfant-Jesus) and Laval University Cancer Research Center, Qu\u00e9bec City, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Fitieh","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada."},{"name":"Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2733-7052","authenticated-orcid":true,"given":"J. N. Mark","family":"Glover","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Yves","family":"Masson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Medical Biochemistry and Pathology, CHU de Qu\u00e9bec Research Centre (Oncology Division, H\u00f4pital Enfant-Jesus) and Laval University Cancer Research Center, Qu\u00e9bec City, Quebec, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5526-6063","authenticated-orcid":true,"given":"Ismail Hassan","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Oncology, Faculty of Medicine &amp; Dentistry, University of Alberta, 11560 University Avenue, Edmonton T6G 1Z2, Alberta, Canada."},{"name":"Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00452-3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)38654-4"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.11.3977-3987.2000"},{"key":"e_1_3_2_5_2","first-page":"5077","article-title":"Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin","volume":"49","author":"Hsiang Y. H.","year":"1989","unstructured":"Y. H. Hsiang, M. G. Lihou, L. F. Liu, Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res. 49, 5077\u20135082 (1989).","journal-title":"Cancer Res."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003910"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09196-9"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","unstructured":"M. Honda M. Razzaghi P. Gaur E. Malacaria L. Di Biagi F. A. Aiello E. A. Paintsil A. Stanfield B. J. Deppe L. Gakhar N. J. Schnicker M. A. Spies P. Pichierri M. Spies A double-ring of human RAD52 remodels replication forks restricting fork reversal. bioRxiv 566657 (2024). https:\/\/doi.org\/10.1101\/2023.11.14.566657.","DOI":"10.1101\/2023.11.14.566657"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.748033"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07312"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.08.037"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09355"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09318"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.2003811"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2010.09.015"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20120307"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.08.006"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09399"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1904"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1905"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.391"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016600"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cancerbio-030617-050502"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12585"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12584"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp244"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201406099"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-018-0075-z"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.11.022"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.03.041"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01180-5"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01164-5"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3417"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.09.036"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.08.010"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202106022"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.04.031"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.07.001"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.214080.113"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1839909"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.048330"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.05.015"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00863-09"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.05.024"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.178459.111"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12256"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5844"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201104003"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08467"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00670"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature18325"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm1059"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12889"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa723"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03801-1"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00297-8"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.193"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.05854-11"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw557"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002271"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.05.026"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.308254.117"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.004769"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02144-5"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0126598"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2258"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-46279-5"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.35528"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201709121"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/narcan\/zcab003"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-998-3_27"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32743-w"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07729-2"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/9.18.4709"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303952200"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2018.04.002"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.225045.113"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2015.03.007"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.2994"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2016.04.019"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.04.014"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202300108"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.115"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-1680-1_10"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2076"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.22215"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.09.014"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.01.021"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2011.07.009"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2007.02.032"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.20.11364"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000881200"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv279"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.03.025"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14620-6"},{"key":"e_1_3_2_97_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2013.05.026"},{"key":"e_1_3_2_98_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.10.038"},{"key":"e_1_3_2_99_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.11.027"},{"key":"e_1_3_2_100_2","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12617"},{"key":"e_1_3_2_101_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14135"},{"key":"e_1_3_2_102_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.010"},{"key":"e_1_3_2_103_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2021.01.008"},{"key":"e_1_3_2_104_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0152-0"},{"key":"e_1_3_2_105_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03443"},{"key":"e_1_3_2_106_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03445"},{"key":"e_1_3_2_107_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002310"},{"key":"e_1_3_2_108_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1129"},{"key":"e_1_3_2_109_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.07.010"},{"key":"e_1_3_2_110_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.03.058"},{"key":"e_1_3_2_111_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200802146"},{"key":"e_1_3_2_112_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3259"},{"key":"e_1_3_2_113_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0862"},{"key":"e_1_3_2_114_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3578"},{"key":"e_1_3_2_115_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb1267"},{"key":"e_1_3_2_116_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.15"},{"key":"e_1_3_2_117_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.105709"},{"key":"e_1_3_2_118_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107880"},{"key":"e_1_3_2_119_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1232"},{"key":"e_1_3_2_120_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr800468j"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adv0381","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T17:59:38Z","timestamp":1756490378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adv0381"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":119,"journal-issue":{"issue":"35","published-print":{"date-parts":[[2025,8,29]]}},"alternative-id":["10.1126\/sciadv.adv0381"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adv0381","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]},"assertion":[{"value":"2024-12-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadv0381"}}