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Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair. Histone H2AX has a known role in DNA damage repair but interestingly, its loss is associated with resistance to poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-deficient tumours. Here, the authors identify a role of γH2AX in the degradation of replication forks and demonstrate that H2AX loss drives PARP inhibitor resistance via increased stressed fork stability in BRCA-deficient tumours.

Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signaling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38α stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1-p38α activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1-p38α in fork protection. We further reveal that Brca1-deficient mammary tumor cells that have acquired PARPi resistance regain chemosensitivity after PIN1 or p38α inhibition. Collectively, our findings identify the PIN1-p38-CtIP signaling pathway as a critical regulator of replication fork integrity.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs)1,2. In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA13–6. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours7,8, we identify a novel function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-dependent replication fork degradation is elicited by the inhibition of CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection of stalled forks. In summary, our results demonstrate a novel role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

The purpose of this paper is to highlight the hydrogeological contact among aquifers in karst and fissured systems and study the different flowpaths present in said aquifers; given the complex hydrogeological and tectonics settings, detailed surveys in the Umbria-Marche limestone ridges and tracer field tests were used to achieve this goal. DNA and fluorescent tracers were injected into a sinkhole and thereafter recovered at different points, allowing both for the identification of contact among aquifers, as well as the main and secondary directions of groundwater. The tracer tests have shown that the majority of the groundwater flow is directed towards the axis of the tectonic structures, emerging in more depressed areas. In addition, they have confirmed the influence of karstification on the recharge, which allows for a more detailed characterisation of water circulation in the unsaturated zone of the Maiolica and the Calcare Massiccio limestone aquifers thus offering confirmation of the hydrogeological survey results, and providing additional information that was previously unknown. Furthermore, the DNA tracer provided good results in the field especially in the karst systems and fissured rocks, thus confirming its appropriacy for flowpath investigations and vulnerability analyses of springs. In particular, DNA is suitable for very large amounts of groundwater owing to its very low detection limit. Further investigations and studies are, however, required to assess its validity also for the evaluation of hydrogeological parameters.

A seismic sequence in central Italy from August 2016 to January 2017 affected groundwater dynamics in fractured carbonate aquifers. Changes in spring discharge, water-table position, and streamflow were recorded for several months following nine Mw 5.0–6.5 seismic events. Data from 22 measurement sites, located within 100 km of the epicentral zones, were analyzed. The intensity of the induced changes were correlated with seismic magnitude and distance to epicenters. The additional post-seismic discharge from rivers and springs was found to be higher than 9 m3/s, totaling more than 0.1 km3 of groundwater release over 6 months. This huge and unexpected contribution increased streamflow in narrow mountainous valleys to previously unmeasured peak values. Analogously to the L’Aquila 2009 post-earthquake phenomenon, these hydrogeological changes might reflect an increase of bulk hydraulic conductivity at the aquifer scale, which would increase hydraulic heads in the discharge zones and lower them in some recharge areas. The observed changes may also be partly due to other mechanisms, such as shaking and/or squeezing effects related to intense subsidence in the core of the affected area, where effects had maximum extent, or breaching of hydraulic barriers.

In the current context of the energy transition, the reuse of offshore oil and gas (O&G) structures that have reached the end of their operational life presents new engineering challenges. Many projects aim to adapt existing facilities for a range of alternative uses. This paper outlines guidelines for identifying the most suitable conversion options aligned with the goals of the ongoing energy transition, focusing on the Italian offshore area. The study promotes the reuse—instead of partial or full removal—of existing offshore platforms originally built for the exploitation of hydrocarbon reservoirs. From an engineering perspective, the project describes the development of guidelines based on an innovative methodology to identify new uses for both offshore oil and gas platforms and the depleted reservoirs, with a focus on safety and environmental impact. The guidelines identify the most suitable and effective conversion option for the platform–reservoir system under consideration. To ensure a realistic approach, the developed methodology allows one to identify the preferable conversion option even when some piece of information is missing or incomplete, as often happens in the early stages of a feasibility study. The screening process provides an associated level of uncertainty related to the degree of data incompleteness. The outcome is a complete evaluation procedure divided into five phases: definition of criteria; assignment of an importance scale to determine how critical each criterion is; connection of indices and weights to each criterion; and analysis of the relationships between them. The guidelines are implemented in a software tool that supports and simplifies the decision-making process. The results are very promising. The developed methodology and the related guidelines applied to a case study have proven to be an effective decision-support for analysts. The study shows that it is possible to identify the most suitable conversion option from a technical, engineering, and operational point of view while also considering its environmental impact and safety implications.

The investigated area, located in the inner part of the Marche region (central Italy) and belonging to the carbote Umbria- Marche ridges in the central Apennines, is characterised by very complex geo-structural setting and widespread karst phenome that make difficult the definition of the relation among the aquifers basing only on the hydrogeological survey. Hence, the presence of different flowpaths among aquifers of the Umbria-Marche hydrostratigraphic sequence and of tectonic contacts among the different structures is verified using tracer tests. In particular, the tests showed that the Calcare Massiccio and the Maiolica aquifers are connected under certain tectonic conditions. A new tracer given by a single stranded D molecule and traditiol fluorescent dyes have been injected into the Montelago sinkhole in different periods (during the recharge and during the discharge) and recovered in several points along the expected hydrogeological basin, using either manual and automatic sampling. Fluorescent traps were positioned in creeks, rivers and springs. The D molecule is useful to trace surface water and groundwater, is detectable even at very low concentrations, no significant change in water density and viscosity can be observed and its use is not dangerous for the environment. The results stress the suitability of D as hydrogeological tracer, capable to identify connections among aquifers and study different flowpaths even in high flow conditions when traditiol tracers are more and more diluted. Moreover, fluorescein tracer allowed for the transport parameter determition, giving mean velocities ranging from 100 to 3000 m/day and mean residence time from some tens to hundreds of hours, and determining the aquifer volumes.