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991.
DNA lesions that block replication fork progression are drivers of cancer-associated genome alterations, but the error-prone DNA repair mechanisms acting on collapsed replication are incompletely understood, and their contribution to genome evolution largely unexplored. Here, through whole-genome sequencing of animal populations that were clonally propagated for more than 50 generations, we identify a distinct class of deletions that spontaneously accumulate in C. elegans strains lacking translesion synthesis (TLS) polymerases. Emerging DNA double-strand breaks are repaired via an error-prone mechanism in which the outermost nucleotide of one end serves to prime DNA synthesis on the other end. This pathway critically depends on the A-family polymerase theta, which protects the genome against gross chromosomal rearrangements. By comparing the genomes of isolates of C. elegans from different geographical regions, we found that in fact most spontaneously evolving structural variations match the signature of polymerase theta-mediated end joining (TMEJ), illustrating that this pathway is an important source of genetic diversification.Identifying the mechanisms that fuel genome change is crucial for understanding evolution and carcinogenesis. Spontaneous mutagenesis is caused predominantly by misinsertions or slippage events of replicative polymerases that are missed by their proofreading domains and not corrected by mismatch repair (Lynch 2008). Less frequently, but with a potentially much more detrimental effect, mutations can arise when DNA damage obstructs progression of DNA replication; and stalled replication forks eventually collapse, resulting in highly mutagenic double-stranded breaks (DSBs). Although error-free homologous repair, in which the sister chromatid is used as a template, restores the original sequence, infrequent but highly mutagenic error-prone end joining processes can give rise to spontaneous deletions and tumor-promoting translocations (Mitelman et al. 2007).To circumvent fork collapse at DNA damage, cells use various alternative polymerases that are capable of incorporating nucleotides across DNA lesions and are hence called translesion synthesis (TLS) polymerases. TLS acts on a wide variety of DNA lesions that can result from endogenous as well as exogenous genotoxic sources: DNA lesions that result from UV-light exposure, for instance, are efficiently bypassed by the well-conserved TLS polymerase eta (pol eta), inactivation of which in humans leads to the variant form of the skin cancer predisposition syndrome, Xeroderma Pigmentosum (Masutani et al. 1999b; Johnson et al. 2007). Abundant in vitro studies demonstrate the involvement of TLS polymerases pol eta and pol kappa in the bypass of lesions that are produced by endogenous reactive compounds, showing that these polymerases are also essential for protection of the genome under unchallenged conditions (Haracska et al. 2000; Fischhaber et al. 2002; Kusumoto et al. 2002).Although error-prone while replicating, and thus potentially causing misinsertions, TLS polymerases are thought to protect cells against the more mutagenic effects of replication fork collapse (Knobel and Marti 2011). Here, we investigate the contribution of TLS polymerases on the maintenance of genome stability and the mechanisms acting on stalled DNA replication by characterizing C. elegans strains that are defective for the Y-family polymerases pol eta and pol kappa. Unexpectedly, we found that DSBs resulting from replication-blocking endogenous lesions are not repaired via canonical DSB repair pathways, but through an error-prone repair mechanism that critically depends on the A-family DNA polymerase theta (pol theta). 相似文献
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Laura K. Murray Stephanie Skavenski Lynn M. Michalopoulos Paul A. Bolton Judith K. Bass Itziar Familiar 《Journal of clinical child and adolescent psychology》2014,43(6):902-914
This study examined Zambian counselors, children, and caregivers’ perceptions of an evidence-based treatment (EBT) for trauma (Trauma-Focused Cognitive Behavioral Therapy [TF-CBT]) utilized in Zambia to address mental health problems in children. Semistructured interviews were conducted with local counselors trained in TF-CBT (N = 19; 90% of those trained; 12 female) and children/caregivers who had received TF-CBT in a small feasibility study (N = 18; 86% of the children and N = 16; 76% of the caregivers) who completed TF-CBT (total completed; N = 21). Each client was asked six open-ended questions, and domain analysis was used to explore the data. Counselors were positive about the program, liked the structure and flexibility, reported positive changes in their clients, and discussed the cultural adaptation around activities and language. Counselors stated the training was too short, and the supervision was necessary. Challenges included client engagement and attendance, availability of location, funding, and a lack of community understanding of “therapy.” Children and caregivers stated multiple positive changes they attributed to TF-CBT, such as better family communication, reduction of problem behaviors, and ability to speak about the trauma. They recommended continuing the program. This study brings a critical examination of providers’ and clients’ perspectives of the implementation of an EBT for children in a low-resource setting. Clinical implications include changing implementation methods based on responses. Research implications include future study directions such as an effectiveness trial of TF-CBT and an examination of implementation factors. 相似文献
993.
Antoine Néel Benoit Henry Sebastien Barbarot Agathe Masseau François Perrin Claire Bernier Xavier Kyndt Xavier Puechal Pierre-Jean Weiller Olivier Decaux Jacques Ninet Arnaud Hot Achille Aouba Leonardo Astudillo Jean-Marie Berthelot Fabrice Bonnet Jean-Marie Brisseau Bérangère Cador Fabienne Closs-Prophette Thomas Dejoie Jean-Dominique de Korwin Robin Dhote Renato Fior Bernard Grosbois Eric Hachulla Pierre-Yves Hatron Henry Jardel David Launay Adrien Lorleac'h Pierre Pottier Guillaume Moulis Jacques Serratrice Amar Smail Mohamed Hamidou 《Autoimmunity reviews》2014,13(10):1035-1041
The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9 years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5 years (range: 1.6-35). Two patients developed Waldenström's macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36 months (range: 2-79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3-4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6 mg/d (range: 5-25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown. 相似文献
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Amir Azarpazhooh Thuan Dao Wendy J. Ungar Faiza Chaudry Rafael Figueiredo Murray Krahn Shimon Friedman 《Journal of endodontics》2014