OSCR

Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion.

Overview

Authors: Eunhye Lee1,2, Wonju Kim1,2, David H Beier3, Yejin Lee1,2, Marina Kovalenko1, Faaiza Saif1, Esaria Oliver1, Bhairavi Srinageshwar1,2, Ryan Murtha1, Marissa A Andrew1, Andrew Jiang1,2, Tammy Gillis1, Brigitte Demelo1, Jayla Ruliera1, Diane Lucente1,2, Seung Kwak4, Ramee Lee4, Ricardo Mouro Pinto1,2,5, Marcy E MacDonald1,2,5, James F Gusella1,2,5,6, Patrick J O’Brien3, Vanessa C Wheeler1,2,5, Ihn Sik Seong1,2
ORCID iDs: Eunhye Lee, Wonju Kim, David H Beier, Esaria Oliver, Andrew Jiang, Ricardo Mouro Pinto, Patrick J O’Brien, Ihn Sik Seong
  1. Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114
  2. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
  3. Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109
  4. CHDI Management Inc., Princeton, NJ 08540
  5. Medical and Population Genetics Program, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142
  6. Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115
Institutions: Harvard University (United States); Massachusetts General Hospital (United States); University of Michigan (United States); Michigan Medicine (United States); Broad Institute (United States); Massachusetts Institute of Technology (United States)
Journal: Proceedings of the National Academy of Sciences of the United States of America, volume 123, issue 10, article e2518854123
Dates: received 14 July 2025; accepted 26 January 2026; published online 2 March 2026; in print 10 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1073/pnas.2518854123 · PMID 41770933 · PMCID PMC12974472 · OpenAlex W7133204233
Open access: hybrid, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics
Keywords: Huntington’s disease, DNA ligase 1, repair fidelity, DNA damage, somatic repeat expansion
MeSH: DNA Ligase ATP*, Huntington Disease*, Trinucleotide Repeat Expansion*, Animals, DNA Repair, Humans, Huntingtin Protein, Mice, Oxidative Stress (* major topic)
Topic: Genetic Neurodegenerative Diseases (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: CHDI Foundation (CHDI JSC); NSF | NSF Graduate Research Fellowship Program (GRFP) (DGE-1841052); HHS | NIH | National Institute of Neurological Disorders and Stroke (NS049206, NS091161, NS127866, NS114065); NINDS NIH HHS (R01 NS114065, R01 NS126420, R01 NS127866); HHS | NIH | National Institute of General Medical Sciences (R35GM149546)
Citations: cited by 1 paper (Europe PMC); 63 references in the paper

Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by inheriting an expanded CAG repeat tract in the huntingtin gene (HTT) that further expands in somatic cells over an individual’s lifetime. Genome-wide association studies have provided critical insight into factors that modify the course of disease. These include DNA repair genes that alter the rate of somatic expansion and other genes that do not appear to directly influence this process. One modifier gene is DNA ligase 1 (LIG1), in which a variant specifying a lysine to asparagine substitution (K845N) is associated with a profound (7 to 8 y) delay in the onset of motor signs. Here, we have taken a multifaceted approach to gain insight into the protective nature of this variant in HD. We demonstrate using in vitro ligase assays and enzyme kinetics that K845N enhances discrimination toward mismatched substrates and increases repair fidelity. Consistent with increased ligation fidelity, K845N confers protection against oxidative stress in cell-based assays. Finally, we demonstrate that the mouse LIG1 K843N orthologue suppresses somatic CAG expansion in HD knock-in mice. Overall, our data provide evidence that altered LIG1 function due to the K845N substitution may contribute to HD clinical delay by slowing somatic expansion in the brain and protecting the genome globally against damage. Significantly, our results provide a mechanistic foundation for considering DNA ligase fidelity as a therapeutic target in HD and potentially in other trinucleotide repeat disorders.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data, Materials, and Software Availability

Duplex sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) under BioProject accession PRJNA1425166 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA1425166) (63). All other data supporting the finding of this study are included in the article and/or SI Appendix (http://www.pnas.org/lookup/doi/10.1073/pnas.2518854123#supplementary-materials).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 23 authors, 5 keywords, 9 MeSH terms, 5 funders, 62 references.

Cite

This paper

Lee, E., Kim, W., Beier, D. H., Lee, Y., Kovalenko, M., Saif, F., Oliver, E., Srinageshwar, B., Murtha, R., Andrew, M. A., Jiang, A., Gillis, T., Demelo, B., Ruliera, J., Lucente, D., Kwak, S., Lee, R., Pinto, R. M., MacDonald, M. E., . . . Seong, I. S. (2026). Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion. Proceedings of the National Academy of Sciences of the United States of America, 123(10), e2518854123. https://doi.org/10.1073/pnas.2518854123

BibTeX

@article{lee2026huntington,
author = {Lee, Eunhye and Kim, Wonju and Beier, David H and Lee, Yejin and Kovalenko, Marina and Saif, Faaiza and Oliver, Esaria and Srinageshwar, Bhairavi and Murtha, Ryan and Andrew, Marissa A and Jiang, Andrew and Gillis, Tammy and Demelo, Brigitte and Ruliera, Jayla and Lucente, Diane and Kwak, Seung and Lee, Ramee and Pinto, Ricardo Mouro and MacDonald, Marcy E and Gusella, James F and O’Brien, Patrick J and Wheeler, Vanessa C and Seong, Ihn Sik},
title = {{Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = mar,
volume = {123},
number = {10},
pages = {e2518854123},
publisher = {National Academy of Sciences},
issn = {0027-8424},
doi = {10.1073/pnas.2518854123},
url = {https://doi.org/10.1073/pnas.2518854123},
pmid = {41770933},
pmcid = {PMC12974472}
}

RIS

TY - JOUR
AU - Lee, Eunhye
AU - Kim, Wonju
AU - Beier, David H
AU - Lee, Yejin
AU - Kovalenko, Marina
AU - Saif, Faaiza
AU - Oliver, Esaria
AU - Srinageshwar, Bhairavi
AU - Murtha, Ryan
AU - Andrew, Marissa A
AU - Jiang, Andrew
AU - Gillis, Tammy
AU - Demelo, Brigitte
AU - Ruliera, Jayla
AU - Lucente, Diane
AU - Kwak, Seung
AU - Lee, Ramee
AU - Pinto, Ricardo Mouro
AU - MacDonald, Marcy E
AU - Gusella, James F
AU - O’Brien, Patrick J
AU - Wheeler, Vanessa C
AU - Seong, Ihn Sik
TI - Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion
T2 - Proceedings of the National Academy of Sciences of the United States of America
J2 - Proc Natl Acad Sci U S A
PY - 2026
DA - 2026/03/02
VL - 123
IS - 10
SP - e2518854123
SN - 0027-8424
PB - National Academy of Sciences
DO - 10.1073/pnas.2518854123
UR - https://doi.org/10.1073/pnas.2518854123
LA - en
ER -

CSL-JSON

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