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- Enervald, E, et al.
(författare)
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A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination
- 2013
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 210:12, s. 2503-2513
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Tidskriftsartikel (refereegranskat)abstract
- DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.
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| 6. |
- Wincent, J, et al.
(författare)
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Sixteen New Cases Contributing to the Characterization of Patients with Distal 22q11.2 Microduplications
- 2010
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Ingår i: Molecular syndromology. - : S. Karger AG. - 1661-8769 .- 1661-8777. ; 1:5, s. 246-254
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Tidskriftsartikel (refereegranskat)abstract
- The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E–H) to the commonly deleted/duplicated region. To date, 21 index cases with ‘distal’ 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit ‘digenic’ model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.
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| 7. |
- Arbuthnott, A., et al.
(författare)
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Reduced opportunities for regional renewal : The role of rigid threat responses
- 2011
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Ingår i: Entrepreneurship and Regional Development. - : Informa UK Limited. - 0898-5626 .- 1464-5114. ; 23:7-8, s. 603-635
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Tidskriftsartikel (refereegranskat)abstract
- This article illustrates how opportunities for regional renewal in a peripheral region may be reduced by rigid threat responses undertaken by established firms operating within traditional regional industry. In an inductive case study of new biorefinery industry initiatives in a region where traditional pulp-and-paper and forestry industry was in decline, we used primary and secondary data to outline how a set of new industry players who created innovative ways of using existing regional infrastructures and resources sparked rigid threat responses among established firms from the struggling traditional industry. Established industry firms framed new industry initiatives as threats, and responded by (1) reducing new industry actors' possibilities for new business development, (2) engaging in entrenched resistance, (3) creating collaborative illusions and (4) undermining the fundamentals of the new industry. Consequently, this study contributes to existing literature by proposing the potential of applying the threat-rigidity thesis on a regional level. This is achieved by illustrating that conflicting behaviours between new and established regional industry actors constrain opportunities for regional renewal in a peripheral region. As such, relevant directions for future research and policy implications are outlined
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