XP mutant power!

Diabetic eye damage may start in bone marrow, suggest Busik and colleagues. Damaged bone marrow nerves and disrupted circadian genes hampered the release of progenitor cells that are required to repair diabetes-induced vessel injury in the eye. Up to 45% of diabetic adults in the US develop retinopathy, a potentially blinding condition. Although high glucose levels and oxidative stress may cause the initial eye injury, Busik et al. suggest that the inability to repair damage causes the real problem. Normally, endothelial progenitor cells (EPCs) exiting the bone marrow help to regenerate damaged vessels during sleep. This nocturnal EPC egress is faulty in patients with diabetes, creating abnormally low levels of nighttime EPCs. Here, the authors show that diabetic rats have similar EPC deficits during the day when they normally sleep. Diabetic rats showed signs of damage to bone marrow nerves, which trigger the signals required for EPC exit. Nerve damage coincided with a drop in the expression of circadian " clock " genes that control the ebb and flow of EPC migration. With fewer reparative EPCs on the move, damaged eye vessels accumulated in diabetic animals. Circadian rhythm disruption has also been blamed for the glucose and blood pressure complications characteristic of diabetes. Because nerve damage and clock gene irregularities preceded eye disease, the authors suggest that the resulting EPC malfunction leads to retinopathy. What triggers nerve damage and circadian disruption is not yet known. Senior author Maria Grant suspects a role for nitric oxide, a known regulator of circadian gene transcription that is commonly elevated in patients with diabetes. Patients with the DNA-repair disorder xeroderma pigmentosum (XP) suffer from a wide range of symptoms; some are mild, such as excessive freckling after sun exposure, whereas others are more severe, including skin cancer and neurodegeneration. Genetic variation underlies this heterogeneity, argue Ueda and colleagues. The so-called " causative " XP mutation (R683W) lies within the transcription complex TFIIH, which helps to transcribe nearly all genes and to repair damaged DNA. The complex includes three subunits with separate enzymatic functions. The R683W mutation is in the XPD subunit and disrupts helicase activity. XP patients can be homozygous or heterozygous for the R683W mutation. And some heterozygotes bear secondary mutations on the opposing XPD allele. Contrary to popular belief, Ueda et al. suggest that these additional mutations matter. Patients with different secondary mutations had different XP symptoms. And their secondary mutations had …