Academic Journal
L Antigen Family Member 3 stabilizes stalled replication forks by reducing MRE11 resection to maintain genome stability.
| Τίτλος: | L Antigen Family Member 3 stabilizes stalled replication forks by reducing MRE11 resection to maintain genome stability. |
|---|---|
| Συγγραφείς: | Lyu M; Dermatology Hospital of Shandong First Medical University, Jinan, Shandong 250022, P.R. China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250022, P.R. China.; School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China., Yang G; School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China., Jia S; School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China., Zhang X; School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China., Li Y; School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China., Feng Y; School of Laboratory Animal and Shandong Laboratory Animal Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China., Lyu X; Dermatology Hospital of Shandong First Medical University, Jinan, Shandong 250022, P.R. China.; Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250022, P.R. China.; Science and Technology Innovation Center, Shandong First Medical University, Jinan, Shandong 250117, P.R. China. |
| Πηγή: | Nucleic acids research [Nucleic Acids Res] 2026 Aug 24; Vol. 54 (16). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1992- : Oxford : Oxford University Press Original Publication: London, Information Retrieval ltd. |
| Ιατρικοί όροι (MeSH): | DNA Replication*/genetics , MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/genetics , Genomic Instability*, Humans ; Mutation |
| Περίληψη: | L Antigen Family Member 3 (LAGE3) is a core component of the KEOPS complex, mutations of which are implicated in Galloway-Mowat syndrome (GAMOS). The KEOPS complex is known to function in telomere maintenance and tRNA N6-threonylcarbamoyladenosine (t6A) modification. However, whether the KEOPS complex also contributes to chromosomal DNA regulation through additional mechanisms remains elusive. Here, we find that LAGE3 and the other four components of KEOPS localize to the stalled forks and protect the nascent DNA strand from degradation under DNA replication stress. TurboID-mediated proximity labeling identifies the MRE11 nuclease as a LAGE3-interacting partner, and LAGE3 deficiency leads to unscheduled stalled forks degradation in an MRE11 nuclease-dependent manner. Similarly, TP53RK, another KEOPS subunit, also exhibits a protective role at stalled forks. In vitro experiments demonstrate that the KEOPS complex prefers to bind to a ds-ssDNA junction, then directly limits MRE11 to degrade nascent DNA. In addition, GAMOS-associated LAGE3 mutations disrupt KEOPS complex assembly, preventing its recruitment to stalled replication forks and consequently leading to unscheduled fork resection and genome instability under DNA replication stress. Collectively, our findings reveal that LAGE3 acts as a stalled fork protector to prevent genome instability during DNA replication stress, providing new insights into GAMOS pathogenesis. (© The Author(s) 2026. Published by Oxford University Press.) |
| References: | Int Immunopharmacol. 2020 Aug;85:106599. (PMID: 32438075) Cold Spring Harb Perspect Biol. 2013 Mar 01;5(3):a012914. (PMID: 23335075) Nat Struct Mol Biol. 2010 Nov;17(11):1305-11. (PMID: 20935632) Curr Protoc Cell Biol. 2020 Dec;89(1):e115. (PMID: 33044803) Front Oncol. 2021 Jan 21;10:553628. (PMID: 33552947) Nat Commun. 2020 Dec 4;11(1):6233. (PMID: 33277478) Nucleic Acids Res. 2019 Jun 20;47(11):5684-5697. (PMID: 30937455) J Biol Chem. 2013 Nov 1;288(44):31458-67. (PMID: 24047897) Int Immunopharmacol. 2021 Jan;90:107267. (PMID: 33310661) Nat Commun. 2019 Sep 3;10(1):3967. (PMID: 31481669) J Cell Biol. 2018 Apr 2;217(4):1521-1536. (PMID: 29475976) Nat Commun. 2023 Feb 1;14(1):526. (PMID: 36720870) Cell Rep. 2016 Aug 16;16(7):2048. (PMID: 27533181) Case Rep Nephrol Dial. 2023 Sep 25;13(1):148-155. (PMID: 37900929) Mol Cell. 2008 Oct 24;32(2):259-75. (PMID: 18951093) Int Immunopharmacol. 2020 Oct;87:106793. (PMID: 32683301) EMBO J. 2006 Aug 9;25(15):3576-85. (PMID: 16874308) Biology (Basel). 2022 Sep 25;11(10):. (PMID: 36290302) Trends Biochem Sci. 2011 Mar;36(3):133-40. (PMID: 20947357) Nucleic Acids Res. 2024 May 8;52(8):4523-4540. (PMID: 38477398) Cell Mol Biol Lett. 2021 Nov 27;26(1):49. (PMID: 34837962) Exp Cell Res. 2014 Nov 15;329(1):85-93. (PMID: 25281304) Mol Cell. 2022 Jun 16;82(12):2298-2314. (PMID: 35714587) Pathol Res Pract. 2023 Aug;248:154700. (PMID: 37473499) Nucleic Acids Res. 2016 Aug 19;44(14):6971-80. (PMID: 27302132) Nat Genet. 2017 Oct;49(10):1529-1538. (PMID: 28805828) FEBS Lett. 2017 Apr;591(8):1083-1100. (PMID: 28079255) Mol Cell. 2017 Sep 7;67(5):867-881.e7. (PMID: 28757209) Mol Cell Biol. 2000 Nov;20(22):8602-12. (PMID: 11046155) Mol Cell. 2005 Jan 7;17(1):153-9. (PMID: 15629726) Nucleic Acids Res. 2021 Nov 8;49(19):10818-10834. (PMID: 34614169) Chromosoma. 2017 Feb;126(1):1-15. (PMID: 26797216) J Cell Biol. 2015 Mar 2;208(5):545-62. (PMID: 25733713) EMBO J. 2021 Jan 15;40(2):e103654. (PMID: 33210317) J Genet Genomics. 2018 May 20;45(5):247-257. (PMID: 29804714) Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313) Nat Biotechnol. 2018 Oct;36(9):880-887. (PMID: 30125270) Cancer Res. 2012 Jun 1;72(11):2814-21. (PMID: 22447567) Nat Struct Mol Biol. 2018 Jun;25(6):446-453. (PMID: 29807999) Commun Biol. 2021 Feb 5;4(1):167. (PMID: 33547416) Cell. 2006 Mar 24;124(6):1155-68. (PMID: 16564010) |
| Grant Information: | 202410 Joint Innovation Team for Clinical & Basic Research; Shandong Academy of Medical Sciences; ZR2024MC179 Natural Science Foundation of Shandong Province |
| Substance Nomenclature: | EC 3.1.- (MRE11 Homologue Protein) 0 (MRE11 protein, human) |
| Entry Date(s): | Date Created: 20260824 Date Completed: 20260824 Latest Revision: 20260826 |
| Update Code: | 20260826 |
| PubMed Central ID: | PMC13501129 |
| DOI: | 10.1093/nar/gkag842 |
| PMID: | 42635129 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1362-4962 |
|---|---|
| DOI: | 10.1093/nar/gkag842 |