The PcrA/UvrD helicase functions in multiple pathways that promote bacterial genome stability including the suppression of conflicts between replication and transcription and facilitating the repair of transcribed DNA. The reported ability of PcrA/UvrD to bind and backtrack RNA polymerase (1,2) might be relevant to these functions, but the structural basis for this activity is poorly understood. In this work, we define a minimal RNA polymerase interaction domain in PcrA, and report its crystal structure at 1.5 Å resolution. The domain adopts a Tudor-like fold that is similar to other RNA polymerase interaction domains, including that of the prototype transcription-repair coupling factor Mfd. Removal or mutation of the interaction domain reduces the ability of PcrA/UvrD to interact with and to remodel RNA polymerase complexes in vitro. The implications of this work for our understanding of the role of PcrA/UvrD at the interface of DNA replication, transcription and repair are discussed.

Highlights d The stem cell transcription factor, ZEB1, demarcates active from quiescent RGL cells d ZEB1 drives the self-renewal of RGL cells by promoting asymmetric cell division d Loss of Zeb1 causes increased neurogenesis and decreased astrogliogenesis d ZEB1 induces Etv5 expression to regulate asymmetric cell division

Adult neural stem cells (aNSCs) are the source for the continuous production of new neurons throughout life. This so-called adult neurogenesis has been extensively studied; the intermediate cellular stages are well documented. Recent discoveries have raised new controversies in the field, such as the notion that progenitor cells hold similar self-renewal potential as stem cells, or whether different types of aNSCs exist. Here, we discuss evidence for heterogeneity of aNSCs, including short-term and long-term self-renewing aNSCs, regional and temporal differences in aNSC function, and single cell transcriptomics. Reviewing various genetic mouse models used for targeting aNSCs and lineage tracing, we consider potential lineage relationships between Ascl1-, Gli1-, and Nestin-targeted aNSCs. We present a multidimensional model of adult neurogenesis that incorporates recent findings and conclude that stemness is a phenotype, a state of properties that can change with time, rather than a cell property, which is static and immutable. We argue that singular aNSCs do not exist.

Identification of initial triggering events in neurodegenerative disorders is critical to the development of preventive therapies. In Huntington’s disease (HD), hyperdopaminergia triggered by dysfunction of inhibitory indirect pathway spiny projection neurons (iSPNs) is believed to induce hyperkinesia, an early-stage HD symptom. Loss of TrkB signalling in iSPNs results in spontaneous motor dysfunction consistent with early HD hyperkinesia. We now show that this is preceded by striatal hyperdopaminergia at the pre-symptomatic stage induced by an increase in midbrain dopaminergic neurons. iSPNs transcriptome analysis revealed de-regulation of metabolic pathways in the absence of TrkB signalling, including up-regulation of Gsto2, encoding the glutathione S-transferase omega-2 (GSTO2). Selective in vivo knockdown of Gsto2 in iSPNs was sufficient to prevent dopaminergic dysfunction and block the onset of HD-like motor symptoms, identifying a functional link between iSPN dysfunction and striatal hyperdopaminergia and a putative disease-modifying enzyme that may be targeted in early stages of HD.