Filamentous nuclear actin regulation of PML NBs during the DNA damage response is deregulated by prelamin A.

Nuclear actin participates in a continuously expanding list of core processes within eukaryotic nuclei, including the maintenance of genomic integrity. In response to DNA damage, nuclear actin polymerises into filaments that are involved in the repair of damaged DNA through incompletely defined mechanisms. We present data to show that the formation of nuclear F-actin in response to genotoxic stress acts as a scaffold for PML NBs and that these filamentous networks are essential for PML NB fission and recruitment of microbodies to DNA lesions.

Runx2 (Runt-Related Transcription Factor 2) Links the DNA Damage Response to Osteogenic Reprogramming and Apoptosis of Vascular Smooth Muscle Cells.

[Figure: see text].

DNA Damage Response: A Molecular Lynchpin in the Pathobiology of Arteriosclerotic Calcification.

Vascular calcification is a ubiquitous pathology of aging. Oxidative stress, persistent DNA damage, and senescence are major pathways driving both cellular and tissue aging, and emerging evidence suggests that these pathways are activated, and even accelerated, in patients with vascular calcification. The DNA damage response-a complex signaling platform that maintains genomic integrity-is induced by oxidative stress and is intimately involved in regulating cell death and osteogenic differentiation in both bone and the vasculature.

Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization.

Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage.

Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state.

The reactive-oxygen-species-(ROS)-generating-enzyme Nox2 is essential for leukocyte anti-microbial activity. However its role in cellular redox homeostasis and, consequently, in modulating intracellular signaling pathways remains unclear. Herein, we show Nox2 activation favors thioredoxin-1 (TRX-1)/p40phox interaction, which leads to exclusion of TRX-1 from the nucleus.

Disruption of PCNA-lamins A/C interactions by prelamin A induces DNA replication fork stalling.

The accumulation of prelamin A is linked to disruption of cellular homeostasis, tissue degeneration and aging. Its expression is implicated in compromised genome stability and increased levels of DNA damage, but to date there is no complete explanation for how prelamin A exerts its toxic effects. As the nuclear lamina is important for DNA replication we wanted to investigate the relationship between prelamin A expression and DNA replication fork stability.

Prelamin A impairs 53BP1 nuclear entry by mislocalizing NUP153 and disrupting the Ran gradient.

The nuclear lamina is essential for the proper structure and organization of the nucleus. Deregulation of A-type lamins can compromise genomic stability, alter chromatin organization and cause premature vascular aging. Here, we show that accumulation of the lamin A precursor, prelamin A, inhibits 53BP1 recruitment to sites of DNA damage and increases basal levels of DNA damage in aged vascular smooth muscle cells.

Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α-mediated stress signaling.

Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine-threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species-generating NADPH oxidase-4 (Nox4) is induced downstream of ATF4, binds to a PP1-targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels.

Sequence-specific and DNA structure-dependent interactions of Escherichia coli MutS and human p53 with DNA.

Many proteins involved in DNA repair systems interact with DNA that has structure altered from the typical B-form helix. Using magnetic beads to immobilize DNAs containing various types of structures, we evaluated the in vitro binding activities of two well-characterized DNA repair proteins, Escherichia coli MutS and human p53. E.