DNA interstrand crosslink (ICL) repair requires a complex network of DNA damage response pathways. Removal of the ICL lesions is vital, as they are physical barriers to essential DNA processes that require the separation of duplex DNA, such as replication and transcription. The Fanconi anemia (FA) pathway is the principal mechanism for ICL repair in metazoans and is coupled to DNA replication. In Saccharomyces cerevisiae, a vestigial FA pathway is present, but ICLs are predominantly repaired by a pathway involving the Pso2 nuclease, which is hypothesized to use its exonuclease activity to digest through the lesion to provide access for translesion polymerases. However, Pso2 lacks translesion nuclease activity in vitro, and mechanistic details of this pathway are lacking, especially relative to FA. We recently identified the Hrq1 helicase, a homolog of the disease-linked enzyme RecQ-like helicase 4 (RECQL4), as a component of Pso2-mediated ICL repair. Here, using genetic, biochemical, and biophysical approaches, including single-molecule FRET (smFRET)– and gel-based nuclease assays, we show that Hrq1 stimulates the Pso2 nuclease through a mechanism that requires Hrq1 catalytic activity. Importantly, Hrq1 also stimulated Pso2 translesion nuclease activity through a site-specific ICL in vitro. We noted that stimulation of Pso2 nuclease activity is specific to eukaryotic RecQ4 subfamily helicases, and genetic and biochemical data suggest that Hrq1 likely interacts with Pso2 through their N-terminal domains. These results advance our understanding of FA-independent ICL repair and establish a role for the RecQ4 helicases in the repair of these detrimental DNA lesions.

Homeostatic regulation of synaptic strength allows for maintenance of neural activity within a dynamic range for proper circuit function. There are largely two distinct modes of synaptic plasticity that allow for homeostatic adaptation of cortical circuits: synaptic scaling and sliding threshold (BCM theory). Previous findings suggest that the induction of synaptic scaling is not prevented by blocking NMDARs, whereas the sliding threshold model posits that the synaptic modification threshold of LTP and LTD readjusts with activity and thus the outcome of synaptic plasticity is NMDAR dependent. Although synaptic scaling and sliding threshold have been considered two distinct mechanisms, there are indications from recent studies that these two modes of homeostatic plasticity may interact or that they may operate under two distinct activity regimes. Here, we report using both sexes of mouse that acute genetic knockout of the obligatory subunit of NMDAR or acute pharmacological block of NMDAR prevents experience-dependent homeostatic regulation of AMPARmediated miniature EPSCs in layer 2/3 of visual cortex. This was not due to gross changes in postsynaptic neuronal activity with inhibiting NMDAR function as determine by c-Fos expression and two-photon Ca 2ϩ imaging in awake mice. Our results suggest that experiencedependent homeostatic regulation of intact cortical circuits is mediated by NMDAR-dependent plasticity mechanisms, which supports a sliding threshold model of homeostatic adaptation.

Cortical areas are highly interconnected both via cortical and subcortical pathways, and primary sensory cortices are not isolated from this general structure. In primary sensory cortical areas, these pre-existing functional connections serve to provide contextual information for sensory processing and can mediate adaptation when a sensory modality is lost. Cross-modal plasticity in broad terms refers to widespread plasticity across the brain in response to losing a sensory modality, and largely involves two distinct changes: cross-modal recruitment and compensatory plasticity. The former involves recruitment of the deprived sensory area, which includes the deprived primary sensory cortex, for processing the remaining senses. Compensatory plasticity refers to plasticity in the remaining sensory areas, including the spared primary sensory cortices, to enhance the processing of its own sensory inputs. Here, we will summarize potential cellular plasticity mechanisms involved in cross-modal recruitment and compensatory plasticity, and review cortical and subcortical circuits to the primary sensory cortices which can mediate cross-modal plasticity upon loss of vision.

Jet lag is a circadian disruption that affects millions of people, resulting, among other things, in extreme sleepiness and memory loss. The hazardous implications of such effects are evident in situations in which focus and attention are required. Remarkably, there is a limited understanding of how jet lag recovery and associated memory loss vary year round under different photoperiods. Here we show, using different cycles representing winter, summer, and equinox in male mice, that jet lag recovery and memory vary significantly with photoperiod changes. We uncover a positive correlation of acute light effects on circadian-driven locomotion (known as negative masking) with photoentrainment speed and memory enhancement during jet lag. Specifically, we show that enhancing or reducing negative masking is correlated with better or worse memory performance, respectively. This study indicates that in addition to timed-light exposure for phase shifting, the negative masking response could also be biologically relevant when designing effective treatments of jet lag.

DNA inter-strand crosslink (ICL) repair requires a complicated network of DNA damage response pathways. Removal of these lesions is vital as they are physical barriers to essential DNA processes that require the separation of duplex DNA, such as replication and transcription. The Fanconi anemia (FA) pathway is the principle mechanism for ICL repair in metazoans and is coupled to replication (1).In Saccharomyces cerevisiae, a degenerate FA pathway is present, but ICLs are predominantly repaired by a pathway involving the Pso2 nuclease that is hypothesized to digest through the lesion to provide access for translesion polymerases (2). However, mechanistic details of this pathway are lacking, especially relative to FA. We recently identified the Hrq1 helicase, a homolog of the diseaselinked RECQL4, as a novel component of Pso2-mediated ICL repair (3). Here, we show that Hrq1 stimulates the Pso2 nuclease in a mechanism that requires Hrq1 catalytic activity. Importantly, Pso2 alone has meagre translesion nuclease activity on an ICL-containing substrate, but digestion through the lesion dramatically increases in the presence of Hrq1. Stimulation of Pso2 nuclease activity is specific to eukaryotic RecQ4 subfamily helicases, and Hrq1 interacts with Pso2, likely through their Ntermini. These results advance our understanding of FA-independent ICL repair and establish a role for the RecQ4 helicases in the repair of these dangerous lesions.