Sarno, Antonio | Search NASA

DOE OSTI2017

Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1

Both a DNA lesion and an intermediate for antibody maturation, uracil is primarily processed by base excision repair (BER), either initiated by uracil-DNA glycosylase (UNG) or by single-strand selective monofunctional uracil DNA glycosylase (SMUG1). The relative in vivo contributions of each glycosylase remain elusive. To assess the impact of SMUG1 deficiency, we measured uracil and 5-hydroxymethyluracil, another SMUG1 substrate, in Smug1 - / - mice. Here, we found that 5-hydroxymethyluracil accumulated in Smug1 - / - tissues and correlated with 5-hydroxymethylcytosine levels. The highest increase was found in brain, which contained about 26-fold higher genomic 5-hydroxymethyluracil levels than the wild type. Smug1 - / - mice did not accumulate uracil in their genome and Ung - / - mice showed slightly elevated uracil levels. Contrastingly, Ung - / - Smug1 - / - mice showed a synergistic increase in uracil levels with up to 25-fold higher uracil levels than wild type. Whole genome sequencing of UNG/SMUG1-deficient tumours revealed that combined UNG and SMUG1 deficiency leads to the accumulation of mutations, primarily C to T transitions within CpG sequences. This unexpected sequence bias suggests that CpG dinucleotides are intrinsically more mutation prone. In conclusion, we showed that SMUG1 efficiently prevent genomic uracil accumulation, even in the presence of UNG, and identified mutational signatures associated with combined UNG and SMUG1 deficiency.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

Dedicated breast computed tomography: Basic aspects

X-ray mammography of the compressed breast is well recognized as the “gold standard” for early detection of breast cancer, but its performance is not ideal. One limitation of screening mammography is tissue superposition, particularly for dense breasts. Since 2001, several research groups in the USA and in the European Union have developed computed tomography (CT) systems with digital detector technology dedicated to x-ray imaging of the uncompressed breast (breast CT or BCT) for breast cancer screening and diagnosis. This CT technology—tracing back to initial studies in the 1970s—allows some of the limitations of mammography to be overcome, keeping the levels of radiation dose to the radiosensitive breast glandular tissue similar to that of two-view mammography for the same breast size and composition. This paper presents an evaluation of the research efforts carried out in the invention, development, and improvement of BCT with dedicated scanners with state-of-the-art technology, including initial steps toward commercialization, after more than a decade of R and D in the laboratory and/or in the clinic. The intended focus here is on the technological/engineering aspects of BCT and on outlining advantages and limitations as reported in the related literature. Prospects for future research in this field are discussed.

60 APPLIED LIFE SCIENCES↗