Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian Atad5

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5+/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5+/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis

Non-random sharing of Plantae genes

The power of eukaryote genomics relies strongly on taxon sampling. This point was underlined in a recent analysis of red algal genome evolution in which we tested the Plantae hypothesis that posits the monophyly of red, green (including plants) and glaucophyte algae. The inclusion of novel genome data from two mesophilic red algae enabled us to robustly demonstrate the sisterhood of red and green algae in the tree of life. Perhaps more exciting was the finding that >1,800 putative genes in the unicellular red alga Porphyridium cruentum showed evidence of gene-sharing with diverse lineages of eukaryotes and prokaryotes. Here we assessed the correlation between the putative functions of these shared genes and their susceptibility to transfer. It turns out that genes involved in complex interactive networks such as biological regulation and transcription/translation are less susceptible to endosymbiotic or horizontal gene transfer, when compared to genes with metabolic and transporter functions

Plant peroxisomal ABC transporters: flexible and unusual

ABC transporters of subfamily D mediate import of substrates for β-oxidation into peroxisomes. Whilst mammals possess three peroxisomal ABCD proteins which homodimerise to form transporters with distinct substrate specificities, Baker’s yeast has a single transporter formed by heterodimerisation, which imports long-chain fatty acyl CoAs. Plants have a single-fused heterodimer transporter that exhibits broad substrate specificity, reflecting the wide range of β-oxidation substrates processed by plants. The fusion appears to have occurred early in the evolution of land plants and was followed by an early duplication event in the monocot lineage. Plant ABCD proteins function in all stages of the life cycle and their physiological roles reflect the ability to transport diverse substrates including saturated and unsaturated fatty acids and aromatic compounds such as precursors of hormones and secondary metabolites. Recent work suggests that transport of CoA substrates involves their cleavage and re-esterification within the peroxisome, thus interaction with appropriate acyl adenylate-activating enzymes potentially provides a mechanism for regulating entry of different substrates into β-oxidation. The mechanism of ABCD transporter targeting is broadly conserved across kingdoms but evidence suggests the regulation of protein turnover differs