232: Lamin A/C steers fork restart via H3K9me3 and PARylation

Cherdyntseva V et al., Nat Commun - Nucleoplasmic Lamin A/C, together with LAP2α, enforces active replication fork slowing during mild replication stress by promoting local H3K9me3 and ADP-ribosylation to restrain RECQ1-mediated restart and protect genome stability. Key terms: Lamin A/C, replication fork, H3K9me3, PARylation, RECQ1.

Study Highlights:
Lamin A/C dynamically associates with replication factories throughout the nucleus and its acute depletion abolishes stress-induced fork slowing and increases chromosomal breakage. Loss of nucleoplasmic Lamin A/C or LAP2α reduces poly-ADP-ribosylation (PAR) at nascent DNA, leading to untimely RECQ1-dependent restart of reversed forks. Mild replication stress induces accumulation of H3K9me3 at replication forks, and Lamin A/C is required to maintain this mark by preventing its removal by the demethylase KDM3A/JMJD1A. Inhibiting G9a to prevent H3K9 methylation phenocopies Lamin A/C loss, reducing PAR at forks and deregulating RECQ1 restart, whereas PARG inhibition or KDM3A downregulation restores PAR levels and fork slowing.

Conclusion:
Nucleoplasmic Lamin A/C maintains local chromatin compaction and PARylation at replication factories to limit RECQ1 activity, enforce fork slowing under mild stress, and preserve genome stability

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Article title:
Nucleoplasmic Lamin A/C controls replication fork restart upon stress by modulating local H3K9me3 and ADP-ribosylation levels

First author:
Cherdyntseva V

Journal:
Nat Commun

DOI:
10.1038/s41467-025-66098-9

Reference:
Cherdyntseva V, Paulson J, González-Acosta D, Ubieto-Capella P, Rodrigues M, Aouami M, Adakli S, Gagné J-P, Bakker C, Poirier GG, Taneja N, Lopes M. Nucleoplasmic Lamin A/C controls replication fork restart upon stress by modulating local H3K9me3 and ADP-ribosylation levels. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66098-9

License:
CC BY 4.0 / Creative Commons Attribution 4.0 International License

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript’s substantive coverage of the Lamin A/C–H3K9me3–PAR axis controlling fork slowdown and RECQ1 restart under mild replication stress, including roles of LAP2α, G9a, KDM3A, and ChromStretch mapping.
- transcript topics: Lamin A/C dynamic interaction with replication factories; Acute Lamin A/C depletion and LAP2α effect on fork slowing; RECQ1-mediated fork restart and genetic rescue by RECQ1 depletion; Local PARylation at replication forks and Lamin A/C control; H3K9me3 accumulation at forks and maintenance by Lamin A/C via KDM3A; G9a-driven chromatin methylation and chromatin compaction

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Lamin A/C dynamically interacts with replication factories throughout the nucleus
- Acute Lamin A/C depletion abolishes active fork slowing under mild replication stress; LAP2α depletion yields a similar pheno...