https://www.selleckchem.com/products/a-1155463.html Persistent protein obstacles on genomic DNA, such as DNA-protein crosslinks (DPCs) and tight nucleoprotein complexes, can block replication forks. DPCs can be removed by the proteolytic activities of the metalloprotease SPRTN or the proteasome in a replication-coupled manner; however, additional proteolytic mechanisms may exist to cope with the diversity of protein obstacles. Here, we show that FAM111A, a PCNA-interacting protein, plays an important role in mitigating the effect of protein obstacles on replication forks. This function of FAM111A requires an intact trypsin-like protease domain, the PCNA interaction, and the DNA-binding domain that is necessary for protease activity in vivo. FAM111A, but not SPRTN, protects replication forks from stalling at poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors, thereby promoting cell survival after drug treatment. Altogether, our findings reveal a role of FAM111A in overcoming protein obstacles to replication forks, shedding light on cellular responses to anti-cancer therapies.Giant rockslides are widespread and sensitive to hydrological forcing, especially in climate change scenarios. They creep slowly for centuries and then can fail catastrophically posing major threats to society. However, the mechanisms regulating the slow-to-fast transition toward their catastrophic collapse remain elusive. We couple laboratory experiments on natural rockslide shear zone material and in situ observations to provide a scale-independent demonstration that short-term pore fluid pressure variations originate a full spectrum of creep styles, modulated by slip-induced undrained conditions. Shear zones respond to pore pressure increments by impulsive acceleration and dilatancy, causing spontaneous deceleration followed by sustained steady-rate creep. Increasing pore pressure results in high creep rates and eventual collapse. Laboratory experiments quantitative