Biology subjects

Watts, L.

Publications and source records attributed to Watts, L..

3 recordsLinked to original sources

bioRxiv2025

The human RIF1-Long isoform interacts with BRCA1 to promote recombinational fork repair under DNA replication stress

RIF1 is a multifunctional protein that regulates DNA replication and repair. RIF1-deficient cells are hypersensitive to DNA replication stress. Of the two alternatively spliced RIF1 isoforms, called RIF1-Short and RIF1-Long, the RIF1-Long isoform is more capable than RIF1-Short in supporting cell recovery from replication stress. Examining replication stress resistance mechanisms specific to RIF1-Long, we find that prolonged replication stress unexpectedly induces interaction of RIF1-Long with BRCA1. Mechanistically, a phosphorylated SPKF motif unique to the RIF1-Long isoform binds the tandem BRCT domain of BRCA1. BRCA1-RIF1-Long interaction is strongly down-regulated through dephosphorylation by RIF1-associated Protein Phosphatase 1. BRCA1-RIF1-Long interaction requires ATR signaling, and occurs predominantly during S phase. Loss of RIF1-Long impairs the formation of RAD51 foci, and reduces the efficiency of homology-mediated repair at broken replication forks. In summary, our investigation establishes RIF1-Long as a new functional binding partner of the BRCA1-BRCT domain, crucial to protect cells from extended DNA replication stress by enabling RAD51-dependent repair of broken replication forks.

molecular biology↗

bioRxiv2025

p16 expression confers sensitivity to CDK2 inhibitors

Blocking the cell cycle is a promising avenue for cancer therapy, with Cyclin-Dependent Kinase 2 (CDK2) emerging as a key target. However, in multiple cell types, CDK4/6 activity compensates for CDK2 inhibition and sustains the proliferative program, enabling CDK2 reactivation. Thus, we hypothesized that sensitivity to CDK2 inhibition is linked to the absence of this CDK4/6-mediated compensatory mechanism. Here we show that Cyclin E1-driven ovarian cancers often co-express the tumor suppressor p16, which inhibits CDK4/6. We show that ovarian cancer cells expressing p16 exhibit heightened sensitivity to CDK2 inhibitors and that depletion of p16 renders them significantly more resistant. Multiplexed immunofluorescence of 225 ovarian patient tumors reveals that at least 18% of tumors express high Cyclin E1 and high p16, a group that we expect to be particularly sensitive to CDK2 inhibition. Thus, p16 may be a useful biomarker for identifying the patients most likely to benefit from CDK2 inhibitors.

cancer biology↗

bioRxiv2022

Interactions between anthropogenic stressors and recurring perturbations mediate ecosystem resilience or collapse

Insights into declines in ecosystem resilience, their causes and effects, can inform pre-emptive action to avoid ecosystem collapse and loss of biodiversity, ecosystem services and human well-being. Empirical studies of ecosystem collapse are rare and hampered by ecosystem complexity, non-linear and lagged responses, and interactions across scales. We investigated how an anthropogenic stressor could diminish ecosystem resilience to a recurring perturbation by altering a critical ecosystem driver. We studied groundwater-dependent, peat-accumulating, fire-prone wetlands in southeastern Australia. We hypothesised that underground mining (stressor) reduced resilience of these wetlands to landscape fires (perturbation) by diminishing groundwater, a key ecosystem driver. We monitored soil moisture as an indicator of ecosystem resilience during and after underground mining and, after a landscape fire, we compared the responses of multiple state variables representing ecosystem structure, composition and function in wetlands within the mining footprint to unmined reference wetlands. Soil moisture showed very strong evidence of decline without recovery in mined swamps, but was maintained in reference swamps through eight years. Relative to burnt reference swamps, burnt and mined swamps showed greater loss of peat via substrate combustion, reduced cover, height and biomass of regenerating vegetation, reduced post-fire plant species richness and abundance, altered plant species composition, increased mortality rates of woody plants, reduced post-fire seedling recruitment, and local extinction of a hydrophilc fauna species. Mined swamps therefore showed strong symptoms of post-fire ecosystem collapse, while reference swamps regenerated vigorously. We conclude that an anthropogenic stressor may diminish the resilience of an ecosystem to recurring perturbations, predisposing it to collapse. Avoidance of ecosystem collapse hinges on early diagnosis of mechanisms and preventative risk reduction. It may be possible to delay or ameliorate symptoms of collapse or to restore resilience, but the latter appears unlikely in our study system due to fundamental alteration of a critical ecosystem driver.

ecology↗