BRCA1 and BRCA2 play a critical role in a variety of molecular processes related to DNA metabolism, including homologous recombination and mediating the replication stress response. Individuals with mutations in the BRCA1 and BRCA2 (BRCA1/2) genes have a significantly higher risk of developing various types of cancers, especially cancers of the breast, ovary, pancreas, and prostate. Currently, the Food and Drug Administration (FDA) has approved four PARP inhibitors (PARPi) to treat cancers with BRCA1/2 mutations. In this review, we will first summarize the clinical outcomes of the four FDA-approved PARPi in treating BRCA1/2 deficient cancers. We will then discuss evidence supporting the hypothesis that the cytotoxic effect of PARPi is likely due to inducing excessive replication stress at the difficult-to-replicate (DTR) genomic regions in BRCA1/2 mutated tumors. Finally, we will discuss the ongoing preclinical and clinical studies on how to combine the PARPi with immuno-oncology drugs to further improve clinical outcomes.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation in the LMNA gene, which results in an alternative splicing defect and the generation of the mutant protein, progerin. Progerin behaves in a dominant-negative fashion, leading to a variety of cellular and molecular changes, including nuclear abnormalities, defective DNA damage response (DDR) and DNA repair, and accelerated telomere attrition. Intriguingly, many of the manifestations of the HGPS cells are shared with normal aging cells. However, at a clinical level, HGPS does not fully match normal aging because of the accelerated nature of the phenotypes and its primary effects on connective tissues. Furthermore, the epigenetic changes in HGPS patients are of great interest and may play a crucial role in the pathogenesis of HGPS. Finally, various treatments for the HGPS patients have been developed in recent years with important effects at a cellular level, which translate to symptomatic improvement and increased lifespan.

POLDIP3 was initially identified as a DNA polymerase delta (Pol δ) interacting protein almost twenty years ago. Intriguingly, it also interacts with proteins involved in a variety of RNA related biological processes, such as transcription, pre-mRNA splicing, mRNA export, and translation. Studies in recent years revealed that POLDIP3 also plays critical roles in disassembling genome wide R-loop formation and activating the DNA damage checkpoint in vivo. Here, we review the functions of POLDIP3 in various RNA and DNA related cellular processes. We then propose a unified model to illustrate how POLDIP3 plays such a versatile role at the crossroad of the RNA and DNA metabolism.

Background In the United States, consumption of a Western diet (WD), high in sugar and fat, has largely contributed to the epidemic of obesity, a major public health problem affecting both males and females. Body mass index (BMI) is a simple index of weight‐for‐height utilized to classify overweight and obesity in humans. However, this index alone is not translational in determining obesity in rodents. Moreover, sex differences in diet‐induced obesity in mice are not well‐characterized. We aim to study temporal metabolic changes in association with body weight gain caused by WD in males and females. Methods Our lab has established a model of WD‐induced obesity in mice. Adult C57BL6 male and female mice were randomized into two experimental groups. The control group (n=7) was fed a standard chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) and the WD group (n=11) was fed a WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 20 weeks. Body weight, BMI, Lee Index (calculated as the cube root of body weight (g)/body length (cm)), intraperitoneal glucose tolerance test (IPGTT), and metabolic cage studies were performed every 4 weeks to study the temporal metabolic changes caused by WD. Results While males showed significant increase in body weight after 3 weeks on WD (31.72g vs. 29.01g control, p<0.05), the obesity state was only confirmed after 8 weeks on WD as shown by increased BMI (4.04 kg/m2 vs. 3.62 kg/m2control, p<0.05). Lee index was significant after 20 weeks on WD (0.34 g/cm vs. 0.33 g/cm control, p<0.05). In comparison to males, female weight gain was delayed and significant after 5 weeks on WD (24.39g vs. 22.00g control, p<0.05). No differences in BMI (3.49 kg/m2 vs. 3.34 kg/m2 control, p=0.43) and Lee index (0.34 g/cm vs. 0.35 g/cm control, p=0.50) were observed even after 16 weeks on WD. Intriguingly, both male and female mice on WD for 20 weeks exhibited decrease in food intake (Male: 2.37 g/day vs. 3.16 g/day control, p<0.05; Female: 2.88 g/day vs. 3.81 g/day control, p<0.05) and caloric intake (Male: 8.98 kcal/day vs. 12.94 kcal/day control, p<0.05; Female: 14.81 kcal/day vs. 15.60 kcal/day control, p=0.60), as well as decreased fecal output (Male: 0.42 wet g/day vs. 2.00 wet g/day control, p<0.05; Female: 0.37 wet g/day vs. 2.17 wet g/day control, p<0.05) and urine output (Male: 1.43 ml/day vs. 2.43 ml/day control, p<0.05; Female: 0.57 ml/day vs. 0.69 ml/day control, p=0.32) compared to their respective controls. Interestingly, males showed significant intolerance to glucose after 2 months on WD (9542 ± 4375 a.u, p<0.05), while females did not show changes in glucose metabolism within 20 weeks of WD protocol. Conclusion Obesity is a complex metabolic disorder whose determination, in murine models, has been simplified to body weight gain. Our results show that significant weight gain alone may not fully characterize the obesity state in mice. Inclusion of other parameters such as BMI, Lee Index, and metabolic profile may better determine experimental obesity in a...

Background Obesity has become a worldwide epidemic and is a major risk factor for the development of cardiovascular disease (CVD). Stiffening in the large arteries, such as the aorta, is a prevalent complication in obesity and frequently precedes hypertension. The mechanism by which obesity contributes to arterial stiffness remains unclear. Peroxisome proliferator‐activated receptor gamma (PPARγ) is a known vasculo‐protective factor. Post‐translational modifications of PPARγ by acetylation can regulate its function. Recently, our group identified that deacetylation of PPARγ enhances vascular endothelial function. We hypothesize that deacetylation of PPARγ protects against obesity‐related arterial stiffness. Methods A mice model of Western diet (WD) induced obesity and our model of deacetylated PPARγ mimetic knock‐in mice with a double lysine to arginine mutation (Lys268Arg, Lys293Arg, termed 2KR mice) were utilized. Adult male C57BL/6 and 2KR mice were randomized into two dietary protocols. Control groups of C57BL/6 (n=8) and 2KR mice (n=5) received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) for 24 weeks. WD groupsof C5 7BL/6 (n=10) and 2KR mice (n= 5) received a WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 24 weeks. Metabolic profiles were assessed by using single‐mouse‐sized metabolic cages. Aortic stiffness was assessed by measuring pulse wave velocity (PWV) with high‐resolution ultrasound, the gold standard for arterial stiffness. Systolic blood pressure was measured using tail cuff plethysmography. Results WD‐induced obesity was confirmed by increased body weight in both WD C57BL/6 mice (36.5g vs. 28.6g controls, p<0.001) and WD 2KR mice groups (44.7g vs. 29.86g controls, p<0.0001). Results obtained from metabolic cages revealed reduction in food, energy and water intake, and urine and fecal output in the WD C57BL/6 and WD 2KR groups as compared to their respective controls. These results indicate that weight gain in WD‐fed mice is not explained by increased energy intake, but rather a reduced metabolic rate. As expected, the WD C57BL/6 group exhibited increased aortic stiffness (5.4 m/s vs. 4.1 m/s controls, p<0.05), which was accompanied by elevated systolic blood pressure (143.8 ± 1.66 vs. 123.5 ± 4.76 mmHg controls, p<0.05). Strikingly, while WD 2KR mice developed obesity, these mice did not exhibit increased aortic stiffness (4.3 m/s vs. 4/4 m/s controls, p=0.89) nor elevated systolic blood pressures (122.4 ± 3.93 mmHg vs. x 115.2 ± 4.15 mmHg controls, p=0.26), indicating that deacetylation of PPARγ protects against aortic stiffness and increases in arterial blood pressure in obesity. Conclusions Our findings demonstrate that while deacetylation of PPARγ does not prevent the development of WD‐induced obesity, it does protect against arterial stiffness in obesity. These results indicate that PPARγ deacetylation is a potential therapeutic strategy in the prevention of obesity‐related arterial stiffness.