BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair.

Tumor suppressor BRCA2 functions in homology-directed repair (HDR), the protection of stalled replication forks, and the suppression of replicative gaps, but their relative contributions to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for fork protection and gap suppression but not HDR. In mice, the loss of fork protection/gap suppression does not compromise genome stability or shorten tumor latency. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection/gap suppression defects are also observed in Brca2 heterozygous cells, likely due to reduced RAD51 stabilization at stalled forks/gaps. Gaps arise from PRIMPOL activity, which is associated with 5-hydroxymethyl-2'-deoxyuridine sensitivity due to the formation of SMUG1-generated abasic sites and is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition. However, HDR proficiency has the major role in mitigating sensitivity to chemotherapeutics, including PARP inhibitors.

Response of tomatoes to inactivated endophyte LSE01 under combined stress of high-temperature and drought.

Endophytes can assist crops in adapting to high temperatures and drought conditions, thereby reducing agricultural losses. However, the mechanism through which endophytes regulate crop resistance to high temperatures and drought stress remains unclear, and concerns regarding safety and stability exist with active endophytes. Thus, heat-treated endophytic bacteria LSE01 (HTB) were employed as a novel microbial fertilizer to investigate their effects on plant adaptation to high temperatures and drought conditions. The results indicated that the diameter and weight of tomatoes treated with HTB under stress conditions increased by 23.04% and 71.15%, respectively, compared to the control. Tomato yield did not significantly decrease compared to non-stress conditions. Additionally, the contents of vitamin C, soluble sugars, and proteins treated with HTB increased by 18.81%, 11.54%, and 99.75%, respectively. Mechanistic research revealed that HTB treatment enhances tomato's stress resistance by elevating photosynthetic pigment and proline contents, enhancing antioxidant enzyme activities, and reducing the accumulation of MDA. Molecular biology research demonstrates that HTB treatment upregulates the expression of drought-resistant genes (GA2ox7, USP1, SlNAC3, SlNAC4), leading to modifications in stomatal conductance, plant morphology, photosynthetic intensity, and antioxidant enzyme synthesis to facilitate adaptation to dry conditions. Furthermore, the upregulation of the heat-resistant gene (SlCathB2-2) can increases the thickness of tomato cell walls, rendering them less vulnerable to heat stress. In summary, HTB endows tomatoes with the ability to adapt to high temperatures and drought conditions, providing new opportunities for sustainable agriculture.

ERG activates a stem-like proliferation-differentiation program in prostate epithelial cells with mixed basal-luminal identity.

To gain insight into how ERG translocations cause prostate cancer, we performed single cell transcriptional profiling of an autochthonous mouse model at an early stage of disease initiation. Despite broad expression of ERG in all prostate epithelial cells, proliferation was enriched in a small, stem-like population with mixed-luminal basal identity (called intermediate cells). Through a series of lineage tracing and primary prostate tissue transplantation experiments, we find that tumor initiating activity resides in a subpopulation of basal cells that co-express the luminal genes Tmprss2 and Nkx3.1 (called BasalLum) but not in the larger population of classical Krt8+ luminal cells. Upon ERG activation, BasalLum cells give rise to the highly proliferative intermediate state, which subsequently transitions to the larger population of Krt8+ luminal cells characteristic of ERG-positive human cancers. Furthermore, this proliferative population is characterized by an ERG-specific chromatin state enriched for NFkB, AP-1, STAT and NFAT binding, with implications for TF cooperativity. The fact that the proliferative potential of ERG is enriched in a small stem-like population implicates the chromatin context of these cells as a critical variable for unmasking its oncogenic activity.