Chromatin in the interphase nucleus moves in a constrained random walk. Despite extensive study, the molecular causes of such movement and its impact on DNA-based reactions are unclear. Using high-precision live fluorescence microscopy in budding yeast, we quantified the movement of tagged chromosomal loci to which transcriptional activators or nucleosome remodeling complexes were targeted. We found that local binding of the transcriptional activator VP16, but not of the Gal4 acidic domain, enhances chromatin mobility. The increase in movement did not correlate strictly with RNA polymerase II (PolII) elongation, but could be phenocopied by targeting the INO80 remodeler to the locus. Enhanced chromatin mobility required Ino80's ATPase activity. Consistently, the INO80-dependent remodeling of nucleosomes upon transcriptional activation of the endogenous PHO5 promoter enhanced chromatin movement locally. Finally, increased mobility at a double-strand break was also shown to depend in part on the INO80 complex. This correlated with increased rates of spontaneous gene conversion. We propose that local chromatin remodeling and nucleosome eviction increase large-scale chromatin movements by enhancing the flexibility of the chromatin fiber.[Keywords: chromatin remodeling; nuclear organization; transcription; VP16; Ino80; fluorescence microscopy; homologous recombination] Supplemental material is available for this article.Received August 15, 2011; revised version accepted January 13, 2012.DNA-based transactions such as transcription, replication, and repair take place in distinct nuclear subcompartments. Transcriptional silencing is frequently associated with the nuclear envelope or occurs near nucleoli (Towbin et al. 2009), whereas the activation of tissue-specific genes correlates with a shift of the relevant genes away from the nuclear periphery (Egecioglu and Brickner 2011). In contrast, genes activated under conditions of nutrient or temperature stress move to nuclear pores when they are induced (Taddei 2007). Finally, some types of damagenamely, irreparable DNA double-strand breaks (DSBs), collapsed replication forks, and eroded telomeres-relocate to nuclear pores to be processed for repair, unlike DSBs that can be repaired by recombination with a homologous template (for review, see Nagai et al. 2010). For these relocalization events to occur, whether at a promoter, a replication fork, or a DSB, chromatin must be mobile.Rapid time-lapse fluorescence microscopy of GFP-LacItagged genomic loci has shown that individual chromosomal domains move constantly in a near-random walk within a restrained volume of the nucleus (Hubner and Spector 2010). The measured radius of constraint for the movement of an average chromosomal locus (;0.6 mm) was roughly similar in every species investigated, although mobility was also shown to be influenced by local chromatin context (Marshall et al. 1997;Heun et al. 2001;Vazquez et al. 2001;Chubb et al. 2002;Gartenberg et al. 2004). For instance, lacO arrays inserted near budding yeast ce...

Persistent DNA double-strand breaks (DSBs) are recruited to the nuclear periphery in budding yeast. Both the Nup84 pore subcomplex and Mps3, an inner nuclear membrane (INM) SUN domain protein, have been implicated in DSB binding. It was unclear what, if anything, distinguishes the two potential sites of repair. Here, we characterize and distinguish the two binding sites. First, DSB-pore interaction occurs independently of cell-cycle phase and requires neither the chromatin remodeler INO80 nor recombinase Rad51 activity. In contrast, Mps3 binding is S and G2 phase specific and requires both factors. SWR1-dependent incorporation of Htz1 (H2A.Z) is necessary for break relocation to either site in both G1- and S-phase cells. Importantly, functional assays indicate that mutations in the two sites have additive repair defects, arguing that the two perinuclear anchorage sites define distinct survival pathways.

Even though a wide range of needs assessment instruments is available, most instruments assess the needs of individuals with subjective cognitive impairment, mild cognitive impairment and dementia on a general level rather than on a more concrete level that may serve better to inform interventions for this growing population. In addition, we suggest basing the development of instruments firmly on an adequate theoretical framework and standardised procedural guidelines.

BackgroundMotivational abilities (MA), that describe skills in relation to goal-oriented behavior, have recently been found to be associated with neuropathological aging. Here we examine the impact of MA on the long-term course of mild cognitive impairment (MCI).MethodsWe followed-up N = 64 individuals diagnosed with MCI (Mage = 73 years, 44% female) for 3 years. MA were assessed by long-term informants of the participants using two scales: motivation and decision regulation [Volitional Components Questionnaires, VCQ, (Kuhl and Fuhrmann, Decomposing self-regulation and self-control: the volitional components inventory, 1998)]. Cognitive abilities were assessed with the Mini Mental State Examination (J Psychiatr Res 12:189-98, 1975). Survival analyses and multilevel modeling (MLM) were applied to determine the predicting effect of informant-rated MA at baseline on the likelihood of MCI stability and on the trajectory of cognitive abilities.ResultsFifty percent (n = 32) of the MCI participants remained stable, while 32.8% (n = 21) and 17.2% (n = 11) converted to Alzheimer’s disease (AD) or dropped-out, respectively. Survival analyses revealed that MCI cases with higher-rated MA at baseline were more likely to exert a stable course in MCI over 3 years (p = 0.036) when controlling for demographic characteristics and executive function. MLM analyses indicated that higher informant-rated MA at baseline were significantly related to higher cognitive abilities, even when controlling for MCI subtype (p = 0.030).ConclusionsThis study provides preliminary longitudinal evidence for a lower risk of conversion to AD and higher cognitive abilities by higher rated MA at an early stage of MCI.