Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry

Cells adapt to familiar changes in their environment by activating predefined regulatory programs that establish adaptive gene expression states. These hard-wired pathways, however, may be inadequate for adaptation to environments never encountered before. Here, we reveal evidence for an alternative mode of gene regulation that enables adaptation to adverse conditions without relying on external sensory information or genetically predetermined cis-regulation. Instead, individual genes achieve optimal expression levels through a stochastic search for improved fitness. By focusing on improving the overall health of the cell, the proposed stochastic tuning mechanism discovers global gene expression states that are fundamentally new and yet optimized for novel environments. We provide experimental evidence for stochastic tuning in the adaptation of Saccharomyces cerevisiae to laboratory-engineered environments that are foreign to its native gene-regulatory network. Stochastic tuning operates locally at individual gene promoters, and its efficacy is modulated by perturbations to chromatin modification machinery

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair

UV-sensitive syndrome (UVSS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma1, 2, 3, 4. Despite mild clinical features, cells from individuals with UVSS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER)2, 4, 5, which removes DNA damage in actively transcribed genes6. Three of the seven known UVSS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)7, 8. The remaining four individuals with UVSS, one of whom is described for the first time here, formed a separate UVSS-A complementation group1, 9, 10; however, the responsible gene was unknown. Using exome sequencing11, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders

On the nature of low temperature internal friction peaks in metallic glasses

Low temperature (30 <T <300 K) internal friction in a metallic glass Ni60Nb40 subjected to preliminary inhomogeneous deformation by cold rolling, homogeneous tensile deformation or electrolytic charging with hydrogen is investigated. Cold rolling or hydrogenation result in appearance of similar internal friction peaks and hysteresis damping. Homogeneous deformation has no influence on low temperature internal friction. The phenomenon of microplastic deformation during hydrogenation of weakly stressed samples is revealed. It is argued that microplastic deformation of metallic glasses during hydrogenation without external stress takes place too. Plastic how both on cold rolling and hydrogenation occurs via formation and motion of dislocation-like defects which are the reason of the observed anelastic anomalies. It is concluded that low temperature internal friction peaks described in the literature for ''as-cast'', cold deformed and hydrogenated samples have common dislocation-like origin