Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1)1–7 in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis1–7. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. Cells derived from patients with SPRTN mutations elicit genomic instability and people afflicted with this syndrome developed hepatocellular carcinoma. Here we describe the molecular mechanism by which SPRTN contributes to genome stability and normal cellular homeostasis. We show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)— a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs. Upon DNA and ubiquitin binding, SPRTN can elicit proteolytic activity; cleaving DPC substrates and itself. SPRTN null cells or cells derived from patients with Ruijs-Aalfs syndrome are impaired in the resolution of covalent DPCs in vivo. Collectively, SPRTN is a mammalian protease required for resolving DNA-protein crosslinks in vivo whose function is compromised in Ruijs-Aalfs syndrome patients.DOI: http://dx.doi.org/10.7554/eLife.21491.001

The purpose of this study was 1) to answer whether the reduction in spleen size in breath-hold apnea is an active contraction or a passive collapse secondary to reduced splenic arterial blood flow and 2) to monitor the spleen response to repeated breath-hold apneas. Ten trained apnea divers and 10 intact and 7 splenectomized untrained persons repeated five maximal apneas (A1-A5) with face immersion in cold water, with 2 min interposed between successive attempts. Ultrasonic monitoring of the spleen and noninvasive cardiopulmonary measurements were performed before, between apneas, and at times 0, 10, 20, 40, and 60 min after the last apnea. Blood flows in splenic artery and splenic vein were not significantly affected by breath-hold apnea. The duration of apneas peaked after A3 (143, 127, and 74 s in apnea divers, intact, and splenectomized persons, respectively). A rapid decrease in spleen volume ( approximately 20% in both apnea divers and intact persons) was mainly completed throughout the first apnea. The spleen did not recover in size between apneas and only partly recovered 60 min after A5. The well-known physiological responses to apnea diving, i.e., bradycardia and increased blood pressure, were observed in A1 and remained unchanged throughout the following apneas. These results show rapid, probably active contraction of the spleen in response to breath-hold apnea in humans. Rapid spleen contraction and its slow recovery may contribute to prolongation of successive, briefly repeated apnea attempts.

These findings indicate that, in moderately trained athletes, postexercise hypotension is associated primarily with reduced cardiac output because of reduced stroke volume, suggesting venous pooling. In addition, the occurrence of hypotension is more frequent in trained subjects with lower cardiopulmonary fitness level or higher resting SBP.

We have previously shown in a rat model that a single bout of high-intensity aerobic exercise 20 h before a simulated dive reduces bubble formation and after the dive protects from lethal decompression sickness. The present study investigated the importance of these findings in man. Twelve healthy male divers were compressed in a hyperbaric chamber to 280 kPa at a rate of 100 kPa min −1 breathing air and remaining at pressure for 80 min. The ascent rate was 9 m min −1 with a 7 min stop at 130 kPa. Each diver underwent two randomly assigned simulated dives, with or without preceding exercise. A single interval exercise performed 24 h before the dive consisted of treadmill running at 90% of maximum heart rate for 3 min, followed by exercise at 50% of maximum heart rate for 2 min; this was repeated eight times for a total exercise period of 40 min. Venous gas bubbles were monitored with an ultrasonic scanner every 20 min for 80 min after reaching surface pressure. The study demonstrated that a single bout of strenuous exercise 24 h before a dive to 18 m of seawater significantly reduced the average number of bubbles in the pulmonary artery from 0.98 to 0.22 bubbles cm −2 (P = 0.006) compared to dives without preceding exercise. The maximum bubble grade was decreased from 3 to 1.5 (P = 0.002) by pre-dive exercise, thereby increasing safety. This is the first report to indicate that pre-dive exercise may form the basis for a new way of preventing serious decompression sickness.