Chronic lymphocytic leukaemia (CLL) results from the accumulation of apoptosis-resistant clonal B cells that are arrested in G0/G1, and is heterogeneous with respect to clinical outcome. An aggressive form of the disease is identified by an impaired p53 response to ionizing radiation (IR). This is associated with inactivating mutations of either p53 or ATM, a regulator of p53 activated by IR-induced DNA damage. Since other forms of DNA damage activate p53 via ATR, a kinase closely related to ATM, abnormalities of the ATR-p53 pathway also have the potential to result in p53 dysfunction. We therefore tested cases of CLL for abnormal p53 responses to ultraviolet irradiation (UVC), a known activator of ATR, to screen for additional forms of p53 dysfunction. CLL cells and normal peripheral blood mononuclear cell (PBMC) preparations (predominantly noncycling lymphocytes) were treated with UVC and assessed for p53 responses. In all of the CLL cases and PBMC preparations tested, we were unable to detect p53 accumulation, phosphorylation or transcriptional consequences in response to UVC-induced DNA damage. The most likely explanation for the absence of UVC-induced p53 activation in CLL and normal lymphocytes was that, in contrast to other cell types, the UVC-induced ATR pathway was inactive. This notion was confirmed by showing that ATR protein was absent or undetectable in all of the cases of CLL and normal PBMCs screened. This was an unexpected finding because ATR was thought to be essential for the viability of somatic cells and for normal human and murine embryonic development. An obvious difference between the cell lines used as positive controls for ATR antibodies and the CLL cells/PBMCs was that the former were actively cycling while the latter were quiescent. We therefore hypothesized that the ATR-p53 pathway is selectively downregulated in noncycling lymphocytes. To test this, we induced cycling in the T-cell fraction of PBMC preparations and demonstrated that ATR protein expression was restored. Furthermore, p53 was upregulated and phosphorylated in response to UVC in these cells. Our data support the conclusion that the ATR-p53 pathway is suppressed in noncycling lymphocytes via ATR downregulation. We tentatively suggest that this repressed DNA damage response may have evolved to protect quiescent lymphocytes from the potential for p53-dependent apoptosis in the face of some forms of endurable genotoxic stress. If this is the case, DNA repair and genome stability might be compromised in quiescent lymphocytes with potentially negative consequences.
Page 90 THE EXCAVATIONS 92 EARLIER PREHISTORIC ACTIVITY 104 THE IRON AGE SETTLEMENT 104 LATE IRON AGE AND ROMANO-BRITISH SETTLEMENT 117 MEDIEVAL AND LATER ACTIVITY 124 THE FINDS 124 APPENDIX: INDEX TO MICROFICHE 133 The report on partial rescue excavations of the Collfryn enclosure between 1980-81 presents a summary of the first large-scale investigation of one of the numerous semi-defensive cropmark and earthwork enclosure sites in the upper Severn valley in mid-Wales. Earlier prehistoric activity of an ephemeral nature is represented by a scattering of Mesolithic and Late Neolithic or early Bronze Age flintwork, and by a pit containing sherds of several different Beaker vessels. The first enclosed settlement, constructed in about the 3rd century be probably consisted of three widely-spaced concentric ditches, associated with banks of simple dump construction, having a single gated entranceway on the downhill side. It covered an area of about 2.5 ha and appears to have been of a relatively high social status, and appropriate in size for a single extended-family group. This was subsequently reduced in about the ist century be to a double-ditched enclosure, by the recutting of the original inner ditch and the cutting of a new ditch immediately outside it. The habitation area between the 3 rd and ist centuries be probably focused on timber buildings in the central enclosure of about 0.4 ha, whose gradually evolving pattern appears to have comprised between 3-4 roundhouses and 4-5 four-posters at any one time. Little excavation was undertaken between the outer ditches of the first phase settlement, but these are assumed to have been used as stock enclosures. A mixed 1 The Clwyd-Powys Archaeological Trust, 7a Church Street, Welshpool, Powys, SYii 7DL 89 THE PREHISTORIC SOCIETY farming economy is suggested by cattle, sheep/goat and pig remains, and remains of glume wheats, barley and oats. Industries included small-scale iron and bronze-working. The Iron Age settlement was essentially aceramic, although there are significant quantities of a coarse, oxidized ceramic probably representing salt traded from production centres in the Cheshire Plain. The entranceway was remodelled in about the late ist or early 2nd, century AD by means of a timber-lined passage linked to a new gate on the line of the inner bank. There is equivocal evidence of continued occupation within the inner enclosure continuing until at least the mid-^th century AD, possibly at a comparatively low social level, associated with domestic structures of uncertain form sited on earlier roundhouse platforms, and including some four-posters and possible six-posters. Drainage ditches were dug across parts of the site during the Medieval and post-Medieval periods, which were associated with various structures, including a corn-drying kiln inserted into the inner enclosure bank in the 15th century.
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