Severe Combined Immunodeficiency from a Homozygous DNA Ligase 1 Mutant with Reduced Catalytic Activity but Increased Ligation Fidelity.
8-Oxoguanine
LIG1
SCID
autosomal recessive
homozygous
immunophenotyping
magnesium
molecular dynamic simulations
residue interaction network
whole exome sequencing
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
19 Jun 2024
19 Jun 2024
Historique:
received:
30
04
2024
accepted:
10
06
2024
medline:
19
6
2024
pubmed:
19
6
2024
entrez:
19
6
2024
Statut:
epublish
Résumé
A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.
Identifiants
pubmed: 38896336
doi: 10.1007/s10875-024-01754-1
pii: 10.1007/s10875-024-01754-1
doi:
Substances chimiques
DNA Ligase ATP
EC 6.5.1.1
LIG1 protein, human
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
151Subventions
Organisme : King Abdullah University of Science and Technology
ID : CRG8 URF/1/4036-01-01
Organisme : King Abdullah University of Science and Technology
ID : CRG8 URF/1/4036-01-01
Informations de copyright
© 2024. The Author(s).
Références
Tomkinson AE, Naila T, Khattri Bhandari S. Altered DNA ligase activity in human disease. Mutagenesis. 2020;35(1):51–60.
Ellenberger T, Tomkinson AE. Eukaryotic DNA ligases: structural and functional insights. Annu Rev Biochem. 2008;77:313–38.
doi: 10.1146/annurev.biochem.77.061306.123941
Lu G, et al. Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining. Proc Natl Acad Sci U S A. 2016;113(5):1256–60.
doi: 10.1073/pnas.1521597113
Masani S, et al. Redundant function of DNA ligase 1 and 3 in alternative end-joining during immunoglobulin class switch recombination. Proc Natl Acad Sci U S A. 2016;113(5):1261–6.
doi: 10.1073/pnas.1521630113
Blair K, et al. Mechanism of human Lig1 regulation by PCNA in Okazaki fragment sealing. Nat Commun. 2022;13(1):7833.
doi: 10.1038/s41467-022-35475-z
Pascal JM, et al. Human DNA ligase I completely encircles and partially unwinds nicked DNA. Nature. 2004;432(7016):473–8.
doi: 10.1038/nature03082
Sun D, et al. Elevated expression of DNA ligase I in human cancers. Clin Cancer Res. 2001;7(12):4143–8.
Montecucco A, et al. DNA ligase I gene expression during differentiation and cell proliferation. Nucleic Acids Res. 1992;20(23):6209–14.
doi: 10.1093/nar/20.23.6209
Barnes DE, et al. Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell. 1992;69(3):495–503.
doi: 10.1016/0092-8674(92)90450-Q
Webster AD, et al. Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene. Lancet. 1992;339(8808):1508–9.
doi: 10.1016/0140-6736(92)91266-B
Prigent C, et al. Aberrant DNA repair and DNA replication due to an inherited enzymatic defect in human DNA ligase I. Mol Cell Biol. 1994;14(1):310–7.
Maffucci P, et al. Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies. J Clin Invest. 2018;128(12):5489–504.
doi: 10.1172/JCI99629
Tang Q, Kamble P, Caglayan M. DNA ligase I variants fail in the ligation of mutagenic repair intermediates with mismatches and oxidative DNA damage. Mutagenesis. 2020;35(5):391–404.
doi: 10.1093/mutage/geaa023
Dabrowska-Leonik N, et al. Case report: severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation. Front Immunol. 2022;13:1033338.
doi: 10.3389/fimmu.2022.1033338
Schatorje EJ, et al. Paediatric reference values for the peripheral T cell compartment. Scand J Immunol. 2012;75(4):436–44.
doi: 10.1111/j.1365-3083.2012.02671.x
Shearer WT, et al. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112(5):973–80.
doi: 10.1016/j.jaci.2003.07.003
Rogakou EP, et al. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273(10):5858–68.
doi: 10.1074/jbc.273.10.5858
Punwani D, et al. Lentivirus mediated correction of artemis-deficient severe combined immunodeficiency. Hum Gene Ther. 2017;28(1):112–24.
doi: 10.1089/hum.2016.064
Tumbale PP, et al. Two-tiered enforcement of high-fidelity DNA ligation. Nat Commun. 2019;10(1):5431.
doi: 10.1038/s41467-019-13478-7
Silva JMF, et al. Haematopoietic stem cell transplantation for DNA ligase 1 deficiency. J Clin Immunol. 2021;41(1):238–42.
doi: 10.1007/s10875-020-00871-x
Raducanu VS, et al. Mechanistic investigation of human maturation of Okazaki fragments reveals slow kinetics. Nat Commun. 2022;13(1):6973.
doi: 10.1038/s41467-022-34751-2
Ba X, Boldogh I. 8-Oxoguanine DNA glycosylase 1: beyond repair of the oxidatively modified base lesions. Redox Biol. 2018;14:669–78.
doi: 10.1016/j.redox.2017.11.008
Fortini P, et al. 8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways. Mutat Res. 2003;531(1–2):127–39.
doi: 10.1016/j.mrfmmm.2003.07.004
Teo IA, et al. Multiple hypersensitivity to mutagens in a cell strain (46BR) derived from a patient with immuno-deficiencies. Mutat Res. 1983;107(2):371–86.
doi: 10.1016/0027-5107(83)90177-X
Levin DS, et al. Interaction between PCNA and DNA ligase I is critical for joining of Okazaki fragments and long-patch base-excision repair. Curr Biol. 2000;10(15):919–22.
doi: 10.1016/S0960-9822(00)00619-9
Soza S, et al. DNA ligase I deficiency leads to replication-dependent DNA damage and impacts cell morphology without blocking cell cycle progression. Mol Cell Biol. 2009;29(8):2032–41.
doi: 10.1128/MCB.01730-08
Morgan MA, Lawrence TS. Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res. 2015;21(13):2898–904.
doi: 10.1158/1078-0432.CCR-13-3229
Smith J, et al. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73–112.
doi: 10.1016/B978-0-12-380888-2.00003-0
Lomax ME, Folkes LK, O’Neill P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin Oncol (R Coll Radiol). 2013;25(10):578–85.
doi: 10.1016/j.clon.2013.06.007