Fritta Brod, Rollenbild, in: Rabindranath Tagore: The King of the dark chamber

Signatur des Originals: S 36/F03237

The role of ATM in the cell cycle control of V(D)J recombination

Lymphocyte development requires the assembly of diversified antigen receptor complexes generated by the genetically programmed V(D)J recombination event. Because germline DNA is cut, introducing potentially dangerous double-stranded breaks (DSBs) and rearranged prior to repair, its activity is limited to the non-cycling stages of the cell cycle, G0/G1. The potential involvement of a key mediator, Ataxia Telangiectasia Mutated or ATM, in the DNA damage response (DDR) and cell cycle checkpoints has been implicated in recombination, but its role is not fully understood. Thymic lymphomas from ATM deficient mice contain clonal chromosomal translocations involving the T-cell antigen receptor (TCR). A previous report found ATM and its downstream target p53 associated with V(D)J intermediates, suggesting the DDR senses recombination. In this study, we sought to understand the role of ATM in V(D)J recombination. Developing thymocytes from ATM deficient mice were analyzed according to the cell cycle to detect V(D)J intermediates. Examination of all TCR loci in the non-cycling (G0/G1) and cycling (S/G2/M) fractions revealed the persistence of intermediates in ATM deficient thymocytes, contrary to the wild-type in which intermediates are found only during G0/G1. Further analysis found no defect in end-joining of intermediates, nor were they detected in developed T-cells. Based upon the presence of persisting intermediates, the recombination initiating nuclease Rag-2 was examined; strict regulation limits it to G 0/G1. Rag-2 regulation was not affected by an ATM deficiency as Rag-2 expression remained contained within G0/G 1, indicating recombination is not continuous. To determine if an ATM deficiency affects recognition of V(D)J breaks, sites of recombination identified by a TCR locus or Rag expression were analyzed according to co-localization with a DDR factor phosphorylated immediately after DNA damage, phosphorylated H2AX (γH2AX). No differences in co-localization were found between the wild-type and ATM deficiency, demonstrating ATM deficient lymphocytes retain the ability to recognize DSBs. Together, these results suggest ATM is necessary in the cell cycle regulation of recombination but not essential for the identification of V(D)J breaks. ATM ensures the containment of intermediates within G0/G1 and maintains genomic stability of developing lymphocytes, emphasizing its fundamental role in preventing tumorigenesis.^

Water temperature reconstruction for Terminations I and II of sediment core MD01-2378

We present centennial records of sea surface and upper thermocline temperatures in Core MD01-2378 from the Timor Sea, which provide new insights into the variability of the Indonesian outflow across the last two glacial terminations. Mg/Ca in Globigerinoides ruber (white s. s.) indicates an overall increase of 3.2 °C in sea surface temperature (SST) over Termination I. Following an early Holocene plateau at 11.3-6.4 ka, SSTs cooled by 0.6 °C during the middle to late Holocene (6.4-0.7 ka). The early Holocene warming occurred in phase with increasing northern hemisphere summer insolation, coinciding with northward displacement of the Intertropical Convergence Zone, enhanced boreal summer monsoon and expansion of the Indo-Pacific Warm Pool. Thermocline temperatures (Pulleniatina obliquiloculata Mg/Ca) gradually decreased from 24.5 to 21.5 °C since 10.3 ka, reflecting intensification of a cool thermocline throughflow. The vertical structure of the upper ocean in the Timor Sea evolved in similar fashion during the Holocene and MIS5e, although the duration of SST plateaux differed (11.3 to 6.4 ka in Termination I and from 129 to 119 ka in Termination II), which was probably due to the more intense northern hemisphere summer insolation during MIS 5e. During both terminations, SST increased simultaneously in the southern high latitudes and the tropical eastern Indian Ocean, suggesting virtually instantaneous atmospheric climate feedbacks between the high and low latitudes.