Small-molecule targeting of kinesin-13 KIF2C enhances double-strand break DNA repair and slows down aging
Abstract DNA damage is a central driver of the aging process. We previously found that KIF2C, known to play a role in DNA repair, is repressed in aged cells. Here, we investigated if increased KIF2C activity counteracts DNA damage and its effects on aging phenotypes. We show that a small-molecule agonist of KIF2C enhances DNA repair in two distinct genetic disorders exhibiting DNA damage and accelerated aging, the Hutchinson-Gilford progeria (HGPS) and Down (DS) syndromes. Mechanistically, the KIF2C agonist improves the repair of DNA double-strand breaks by inducing nuclear envelope invaginations poked by cytoplasmic microtubules, which translated into amended epigenetic and transcriptional signatures of HGPS and DS. Moreover, subcutaneous administration of the KIF2C agonist in progeria mice mitigated aging phenotypes, extending their healthspan. Our study discloses a unique geroprotective pharmacological approach targeting DNA damage.
Authors
- Paula Sampaio (ORCID: https://orcid.org/0000-0003-1148-2159)
- Joana Magalhães (ORCID: https://orcid.org/0000-0002-1395-2209)
- Elsa D. Silva (ORCID: https://orcid.org/0000-0001-5113-7355)
- Carlos Sousa-Soares (ORCID: https://orcid.org/0000-0003-1877-5325)
- Francisco Vasques‐Nóvoa (ORCID: https://orcid.org/0000-0001-9701-8538)
- Rui Ribeiro (ORCID: https://orcid.org/0000-0003-3759-2399)
- Elsa Logarinho (ORCID: https://orcid.org/0000-0002-8741-0744)
- Vera A. Gorbunova (ORCID: https://orcid.org/0000-0001-8979-0333)
- Mafalda Sousa (ORCID: https://orcid.org/0000-0003-2238-1070)
- Mafalda Galhardo (ORCID: https://orcid.org/0000-0001-8911-1660)
- Monika Barroso‐Vilares (ORCID: https://orcid.org/0000-0002-4012-3895)
- Andrei Seluanov (ORCID: https://orcid.org/0000-0003-3400-538X)
- Diana Santos Nascimento (ORCID: https://orcid.org/0000-0001-6402-4245)
- Joana Martins‐Macedo (ORCID: https://orcid.org/0000-0003-0442-927X)
- Marcos Antonio Barbosa Da Silva (ORCID: https://orcid.org/0009-0002-6169-3982)
- M. Inês Ala
Institutions
- Universidade do Porto (PT)
- University of Rochester Medical Center (US)
- Hospital de São João (PT)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- Instituto de Biologia Molecular e Celular (PT)
- Instituto Nacional de Engenharia Biomédica (PT)
- Instituto de Ciências Biomédicas Albel Salazar (PT)
- University of Rochester (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1038/s41467-026-79165-6
- Citations
- 2
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Université de Montréal
- Fundação para a Ciência e a Tecnologia
- European Regional Development Fund