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

## TL;DR

Lamin A/C helps cells manage DNA replication during stress by controlling fork restart and maintaining chromosome stability.

## Contribution

Lamin A/C is shown to modulate replication fork dynamics via H3K9me3 and PARylation, linking nuclear architecture to DNA replication stress response.

## Key findings

- Lamin A/C and LAP2α are required for active fork slowing and chromosome stability during mild genotoxic stress.
- Lamin A/C maintains PAR levels at nascent DNA and prevents premature removal of H3K9me3 by JMJD1A/KDM3A.
- H3K9me3 accumulation and PARylation are mechanistically linked to replication fork restart regulation.

## Abstract

Mild replication interference is a consolidated strategy for cancer
chemotherapy. Tolerance to mild replication stress (RS) relies on active fork
slowing, mediated by transient fork reversal and RECQ1-assisted restart, and
modulated by PARP1 and nuclear architectural components via yet-elusive mechanisms.
We combined acute protein inactivation with cell biology and single-molecule
approaches to investigate the role of Lamin A/C upon mild RS. We found that Lamin
A/C dynamically interacts with replication factories throughout the nucleus and,
together with its nucleoplasmic partner LAP2α, is required to induce active fork
slowing and maintain chromosome stability upon mild genotoxic treatments.
Inactivating nucleoplasmic Lamin A/C reduces poly-ADP-ribosylation (PAR) levels at
nascent DNA, triggering deregulated RECQ1-mediated restart of reversed forks.
Moreover, we found that the heterochromatin mark H3K9me3, previously reported at
stalled forks, also accumulates in response to mild RS. H3K9me3 accumulation
requires Lamin A/C, which prevents its premature removal by the histone demethylase
JMJD1A/KDM3A. H3K9me3 loss per se phenocopies Lamin A/C inactivation, reducing PAR
levels and deregulating fork restart by RECQ1. Hence, nucleoplasmic Lamin A/C,
H3K9me3 and PARylation levels are crucial, mechanistically linked modulators of fork
dynamics upon mild RS, with important implications for chemotherapy response and for
Lamin A/C dysfunction in human disease.

Replication fork plasticity upon genotoxic stress is modulated by
nuclear architectural components by elusive mechanisms. Here the authors implicate
Lamin A/C – best known for its structural support of nuclear periphery – in the
control of replication fork restart throughout the nucleus, by supporting
heterochromatin establishment and ADP ribosylation levels at replication
factories.