Roberta Fajka-Boja | PubMed Health

PubMed2026

The function of Mgs1/WRNIP1 in genome maintenance.

Preservation of genomic integrity during replication is challenging, because replication forks are often stalled by several forms of DNA damage or stable secondary DNA structures. Prolonged stalling of the replication fork can lead to incomplete replication, which may induce double strand breaks, genome rearrangements and cell death. Therefore, several DNA repair mechanisms evolved to rescue stalled replication forks, which can elaborate in error-free or error-prone manners. The pathway selection and the fine tuning of the collaboration between different DNA repair proteins involved in the rescue of the stalled replication fork are very important. Based on our recent knowledge, yeast Mgs1 and its human homologue WRNIP1 proteins can be excellent candidates for this fine-tuning regulator function. In this review we summarize our current knowledge about them and try to point out the most important future steps to prove this hypothesis.

DNA repair↗

PubMed2026

PARG inhibition reduces ssDNA levels and limits RPA loading upon replication fork collapse.

Poly(ADP-ribosyl)ation (PARylation) is a transient post-translational modification catalyzed by PARP enzymes and reversed by PARG. PARG inhibition causes sustained PARylation and is being explored as an anticancer strategy, but its cellular consequences remain incompletely understood. Here, we examine how persistent PARylation influences cellular responses to replication stress and DNA damage. We show that sustained PARylation reduces phosphorylated and chromatin-bound RPA most strongly under fork-stalling conditions that progress toward fork collapse. This effect requires PARP1 activity and is restrained by intact ATR-CHK1 signaling, as checkpoint inhibition renders otherwise resistant cells permissive for PARG inhibitor-associated phosphorylated RPA loss from the chromatin. The reduction of RPA phosphorylation is not dependent on BRCA1 and it is not accompanied by increased RAD51 loading. Instead, reduced chromatin-bound RPA coincides with decreased exposed ssDNA. Our results identify a checkpoint-dependent fork-collapse state in which sustained PARylation limits ssDNA and RPA levels.

Replication Protein A↗