Academic Journal
Προβολή σε EDS
Συνδεδεμένο Πλήρες Κείμενο

Differential expression of a disease-associated MRE11 variant reveals distinct phenotypic outcomes.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Differential expression of a disease-associated MRE11 variant reveals distinct phenotypic outcomes.
Συγγραφείς: DeFoer MB; Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200, United States., Mostafa AM; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200, United States.; Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, African Union Authority St., Abbassia, Cairo 11566, Egypt., Hartlerode AJ; Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200, United States.; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200, United States., Orban SK; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200, United States., McDonough K; Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200, United States., Quirk S; Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200, United States., Ferguson BKL; Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200, United States.; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200, United States., Ferguson DO; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2067, Ann Arbor, MI 48109-2200, United States., Sekiguchi JM; Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Rm 2063, Ann Arbor, MI 48109-2200, United States.
Πηγή: Human molecular genetics [Hum Mol Genet] 2025 Nov 18; Vol. 34 (23), pp. 1964-1978.
Τύπος έκδοσης: Journal Article; Research Support, U.S. Gov't, P.H.S.; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
Imprint Name(s): Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
Ιατρικοί όροι (MeSH): MRE11 Homologue Protein*/genetics , MRE11 Homologue Protein*/metabolism , Ataxia Telangiectasia*/genetics , Ataxia Telangiectasia*/pathology, DNA Repair/genetics ; DNA-Binding Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Cycle Proteins/genetics ; DNA Repair Enzymes/genetics ; Humans ; Animals ; Mice ; DNA Breaks, Double-Stranded ; Phenotype ; Mice, Transgenic ; Acid Anhydride Hydrolases
Περίληψη: The MRE11 DNA nuclease plays central roles in the repair of DNA double-strand breaks (DSBs) as a core component of the MRE11-RAD50-NBS1 (MRN) complex. MRN localizes to chromosomal DSBs and recruits and activates the DSB repair protein kinase, ATM, which phosphorylates downstream substrates to elicit cellular DNA damage responses. Pathogenic variants in MRE11 cause the genome instability disorder ataxia-telangiectasia-like disorder (ATLD). The first ATLD patient allele identified, ATLD1, is a nonsense mutation that deletes 76 residues from the MRE11 C-terminus and markedly reduces levels of MRE11-ATLD1 and the entire MRN complex. The MRE11 C-terminus has been demonstrated to function in DNA binding, mediate protein interactions, and undergo post-translational modifications that regulate the MRE11 nuclease. We previously demonstrated that transgenic mice expressing reduced wildtype MRN levels exhibit severe phenotypes, including small body size, anemia, and DNA DSB repair defects. Thus, it is currently unknown whether low MRE11-ATLD1 levels, loss of the C-terminus, or both cause disease-associated phenotypes. In this study, we generated transgenic mouse models that express near endogenous or significantly reduced levels of MRE11-ATLD1 to determine the in vivo importance of the MRE11 C-terminus. We observe that low MRE11-ATLD1 expression leads to anemia, bone marrow failure, extramedullary hematopoiesis, and impaired lymphocyte development, similar to mice expressing low wildtype MRE11. In contrast, higher MRE11-ATLD1 expression results in a subset of moderate phenotypes, indicating that loss of the C-terminus has limited impact on MRN functions in vivo. These findings provide a foundation for predicting the clinical presentation and severity of ATLD patient phenotypes.
(© The Author(s) 2025. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Σχόλια: Update of: bioRxiv. 2025 Jul 18:2025.07.15.664809. doi: 10.1101/2025.07.15.664809.. (PMID: 40791546)
References: Nat Rev Mol Cell Biol. 2021 Dec;22(12):796-814. (PMID: 34429537)
Hum Mol Genet. 2024 Sep 3;33(18):1605-1617. (PMID: 38888340)
J Pediatr. 2009 Sep;155(3):435-8. (PMID: 19732584)
Nat Struct Mol Biol. 2009 Aug;16(8):808-13. (PMID: 19633670)
Mol Cell. 2016 Dec 1;64(5):940-950. (PMID: 27889449)
Cell. 2008 Oct 3;135(1):97-109. (PMID: 18854158)
J Cell Sci. 1998 Dec;111 ( Pt 23):3497-506. (PMID: 9811564)
Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2422720122. (PMID: 40249789)
J Clin Med. 2021 Dec 13;10(24):. (PMID: 34945127)
Nat Struct Mol Biol. 2015 Sep;22(9):736-43. (PMID: 26280532)
Nat Struct Mol Biol. 2009 Aug;16(8):819-24. (PMID: 19633668)
Exp Mol Med. 2024 Mar;56(3):549-558. (PMID: 38443597)
Science. 2000 Dec 8;290(5498):1962-5. (PMID: 11110662)
Mol Cell Biol. 2010 Dec;30(23):5572-81. (PMID: 20921278)
Cell Rep. 2020 Dec 29;33(13):108559. (PMID: 33378670)
Exp Hematol. 2021 Dec;104:9-16. (PMID: 34687807)
Orphanet J Rare Dis. 2012 Feb 28;7:13. (PMID: 22373003)
Nat Struct Mol Biol. 2009 Aug;16(8):814-8. (PMID: 19633669)
J Clin Immunol. 2023 Nov;43(8):2136-2145. (PMID: 37794136)
Nat Rev Mol Cell Biol. 2025 Aug;26(8):586-599. (PMID: 40133633)
Hum Genet. 2022 Dec;141(12):1811-1836. (PMID: 35596788)
Mol Cell. 2023 Jan 19;83(2):167-185.e9. (PMID: 36577401)
JAMA. 2025 Feb 25;333(8):701-714. (PMID: 39869325)
Mol Cell. 2009 Apr 10;34(1):13-25. (PMID: 19362533)
Mol Cell. 2024 Jun 20;84(12):2223-2237.e4. (PMID: 38870937)
Am J Med Genet A. 2014 Jul;164A(7):1830-4. (PMID: 24733832)
Sci Rep. 2018 Jul 4;8(1):10121. (PMID: 29973640)
Sci Adv. 2021 May 21;7(21):. (PMID: 34020942)
J Exp Med. 2009 Mar 16;206(3):669-79. (PMID: 19221393)
Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210. (PMID: 23486281)
Cells. 2020 Jul 13;9(7):. (PMID: 32668560)
Nat Commun. 2023 Sep 16;14(1):5759. (PMID: 37717054)
Nucleic Acids Res. 2011 Mar;39(6):2144-52. (PMID: 21087997)
Mol Cell. 2001 Nov;8(5):1129-35. (PMID: 11741547)
Am J Hum Genet. 2009 May;84(5):605-16. (PMID: 19409520)
Blood Rev. 2024 Nov;68:101225. (PMID: 39107201)
DNA Repair (Amst). 2011 Mar 7;10(3):314-21. (PMID: 21227757)
Cell. 2008 Oct 3;135(1):85-96. (PMID: 18854157)
J Neurol Sci. 2014 Feb 15;337(1-2):219-23. (PMID: 24332946)
Genes Dev. 2002 Jan 15;16(2):159-64. (PMID: 11799059)
Cell. 1999 Dec 10;99(6):577-87. (PMID: 10612394)
Nat Rev Immunol. 2014 Feb;14(2):69-80. (PMID: 24378843)
Nat Struct Mol Biol. 2012 Jan 08;19(2):246-52. (PMID: 22231403)
J Biol Chem. 2009 Apr 3;284(14):9558-65. (PMID: 19202191)
EMBO J. 1998 Nov 2;17(21):6412-25. (PMID: 9799249)
Cell. 2024 Jan 18;187(2):294-311.e21. (PMID: 38128537)
Hum Mol Genet. 2013 Dec 20;22(25):5146-59. (PMID: 23912341)
Mol Cell. 2003 Dec;12(6):1511-23. (PMID: 14690604)
Hum Mol Genet. 2004 Sep 15;13(18):2155-63. (PMID: 15269180)
Mol Cell. 2020 Dec 17;80(6):1013-1024.e6. (PMID: 33338401)
Cell. 2002 May 17;109(4):459-72. (PMID: 12086603)
Grant Information: P30 CA046592 United States CA NCI NIH HHS; R01 HL153068 United States HL NHLBI NIH HHS; R01HL15306801 National Institutes of Health, USA; P30CA046592 The University of Michigan Cancer Center Support
Contributed Indexing: Keywords: DNA repair; genome instability; hematopoiesis; lymphocyte development
Substance Nomenclature: EC 3.1.- (MRE11 Homologue Protein)
0 (MRE11 protein, human)
0 (DNA-Binding Proteins)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
EC 3.6.- (Acid Anhydride Hydrolases)
0 (Cell Cycle Proteins)
EC 6.5.1.- (DNA Repair Enzymes)
Entry Date(s): Date Created: 20251011 Date Completed: 20251119 Latest Revision: 20261017
Update Code: 20261017
PubMed Central ID: PMC13377461
DOI: 10.1093/hmg/ddaf154
PMID: 41075274
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1460-2083
DOI:10.1093/hmg/ddaf154