ABSTRACT
Affinity maturation of the humoral immune response depends on somatic hypermutation (SHM) of immunoglobulin (Ig) genes, which is initiated by targeted lesion introduction by activation-induced deaminase (AID), followed by error-prone DNA repair. Stringent regulation of this process is essential to prevent genetic instability, but no negative feedback control has been identified to date. Here we show that poly(ADP-ribose) polymerase-1 (PARP-1) is a key factor restricting AID activity during somatic hypermutation. Poly(ADP-ribose) (PAR) chains formed at DNA breaks trigger AID-PAR association, thus preventing excessive DNA damage induction at sites of AID action. Accordingly, AID activity and somatic hypermutation at the Ig variable region is decreased by PARP-1 activity. In addition, PARP-1 regulates DNA lesion processing by affecting strand biased A:T mutagenesis. Our study establishes a novel function of the ancestral genome maintenance factor PARP-1 as a critical local feedback regulator of both AID activity and DNA repair during Ig gene diversification.
Subject(s)
Cytidine Deaminase/genetics , Genes, Immunoglobulin/genetics , Immunoglobulin Variable Region/genetics , Poly (ADP-Ribose) Polymerase-1/genetics , Somatic Hypermutation, Immunoglobulin/genetics , Animals , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Cell Line, Tumor , Cells, Cultured , Cytidine Deaminase/metabolism , DNA Damage , DNA Repair , Humans , Mice , Mutation , Poly (ADP-Ribose) Polymerase-1/metabolismABSTRACT
OBJECTIVE: The aim of the study was to assess social cognition in community patients suffering from anorexia nervosa (AN) compared to healthy controls. METHODS: 25 women diagnosed with AN and 25 women matched for education level and age were involved in the study. Both subject groups were assessed using a set of validated experimental tasks, such as the facial expression recognition test, short recognition memory test for faces, 'Reading the mind in the eyes' test. Patients were assessed for symptoms of: eating disorder (the eating attitudes test-EAT-26), OCD (the Yale-Brown obsessive compulsive scale-Y-BOCS) and depression (Beck depression inventory-BDI). The research hypothesis indicated that patients suffering from anorexia represent no significant difference in social cognitive functioning in comparison to the healthy controls. These assessment scales were used to identify whether there are any problems according to social cognitive functioning especially emotion recognition and theory of mind (ToM). The primary outcome assessment was to identify social cognitive deficits in anorexic outpatients and secondary outcome was to verify whether these problems in emotional functioning found in women in acute phase of AN are state or trait effects. RESULTS: Anorexic patients showed significantly higher scores on EAT-26, BDI and Y-BOCS. No significant differences were found in performance of social cognitive tests and facial perception test. DISCUSSION: No marked alterations were found in social cognitive functioning in community patients with average body mass index (BMI) of 17.6. This may indicate that social cognition is a very complex construct to be reliably measured in anorexia nervosa considering relatively limited psychometric data for many social cognitive tasks. Further longitudinal studies are needed to untangle ongoing controversy whether social cognitive deficits in AN could be state or trait related.
ABSTRACT
Activation-induced cytidine deaminase (AID) initiates immunoglobulin diversification in germinal center B cells by targeted introduction of DNA damage. As aberrant nuclear AID action contributes to the generation of B cell lymphoma, the protein's activity is tightly regulated, e.g. by nuclear/cytoplasmic shuttling and nuclear degradation. In the present study, we asked whether DNA damage may affect regulation of the AID protein. We show that exogenous DNA damage that mainly activates base excision repair leads to prevention of proteasomal degradation of AID and hence its nuclear accumulation. Inhibitor as well as knockout studies indicate that activation of poly (ADP-ribose) polymerase (PARP) by DNA damaging agents promotes both phenomena. These findings suggest that PARP inhibitors influence DNA damage dependent AID regulation, with interesting implications for the regulation of AID function and chemotherapy of lymphoma.
