re-write the textbooks: transcription is bidirectional
Genes that contain instructions for making proteins make up less than 2% of the human genome. Yet, for unknown reasons, most of our genome is transcribed into RNA. The same is true for many other organisms that are easier to study than humans. Researchers in the groups of Lars Steinmetz at the European Molecular Biology Laboratory [EMBL] in Heidelberg and Wolfgang Huber at the European Bioinformatics Institute [EMBL-EBI] in Hinxton have now unravelled how yeast generates its transcripts and have come a step closer to understanding their function. The study redefines the concept of promoters [the start sites of transcription] contradicting the established notion that they support transcription in one direction only. The results are also representative of transcription in humans.
Investigating all transcripts produced in a yeast cell, the scientists found that most regions of the yeast genome produce several transcripts starting at the same promoter. These transcripts are interleaved and overlapping on the DNA. In contrast to what was previously thought, the vast majority of promoters seem to initiate transcription in both directions.
Not all of the produced transcripts are stable, many are degraded rapidly making it difficult to observe what they do. While some of the RNA molecules might be ‘transcriptional noise’ without function, other transcripts control the expression of genes and production of proteins. The act of transcription itself is also likely to play an important role in regulation of gene expression. Transcribing one stretch of DNA might either help or in other cases interfere with the transcription of a gene close by. Moreover, transcripts without a current purpose can serve as ‘raw material for evolution’ and acquire new functions over time.
The results shed light on the complex organisation of the yeast genome and the insights gained extend to transcription in humans. A better understanding of transcription mechanisms could find application in new technologies to tune gene regulation in the future.
—EMBL
oxidatively damaged DNA in the germ line
Alberto Velando and colleagues wrote a paper entitled “Avoiding bad genes: oxidatively damaged DNA in germ line and mate choice.”
Below is the abstract:
August Weismann proposed that genetic changes in somatic cells cannot pass to germ cells and hence to next generations. Nevertheless, evidence is accumulating that some environmental effects can promote heritable changes in the DNA of germ cells, which implies that some somatic influence on germ line is possible. This influence is mostly detrimental and related to the presence of oxidative stress, which induces mutations and epigenetic changes. This effect should be stronger in males due to the particular characteristics of sperm. Here, we propose the hypothesis that females are able to avoid males with oxidatively damaged DNA in the germ line by using oxidative-dependent (pre- and post-mating) signals. This new hypothesis may shed light on unsolved questions in evolutionary biology, such as the benefits of polyandry, the lek paradox, or the role of sexual selection on the evolution of aging.
somatic mtDNA mutations
A paper by Alexandra Kukat and Aleksandra Trifunovic demonstrates that somatic mtDNA mutations have the capacity to cause a variety of aging phenotypes in mammals. However, the relative importance of somatic mtDNA mutations in mammalian aging remains unclear, as the overall mutation load in normal mammalian aging tissues is much lower than needed to cause mitochondrial dysfunction. However, results from single cells argue that despite a relatively low overall level of mtDNA mutations, the mutational load in single cells could be substantial. Therefore, this may result in a functional impairment of the tissue by the loss of critical cells by cellular senescence or cell death.
BLAP75/Rmi1
Liudmila Chelysheva and colleagues studied BLAP75/Rmi1 in relation to BLM/Sgs1 and TopoIIIα/Top3. Their paper appeared on the December 2008 issue of PLoS Genetics journal. Below is the summary:
“Recombination is a process by which cells can repair DNA damage. Such repair can either be crossovers (CO), in which DNA molecules are submitted to major exchanges, or non-crossover (NCO) events. Eukaryotic cells have developed several mechanisms to maintain genome stability during vegetative development by limiting the occurrence of CO events in favour of NCO. BLAP75/Rmi1, BLM/Sgs1, and TopoIIIα/Top3 act together in a complex (BTB/RTR) known to be a crucial component of regulation mechanisms against CO formation. However, CO/NCO regulation is thought to be very different during meiosis since homologous chromosomes (paternal and maternal) overcome at least one CO/pair. In this study, we investigate the role of the BTB/RTR complex during meiotic recombination through the analysis of a function of one of its members: the A. thaliana homologue of BLAP75/Rmi1. We show for the first time that BLAP75/Rmi1 is also a key protein of the meiotic homologous recombination machinery. In Arabidopsis, we found that this protein is dispensable for homologous chromosome recognition and synapsis, but necessary for the repair of meiotic double-strand breaks. Furthermore, in the absence of BLAP75, bivalent formation can happen even in the absence of CO.”
Note: A. thaliana blap75 mutants are sterile. They examined the reproductive development of these mutants and found that blap75 sterility is due to abortion of male and female gametophytes. In particular, blap75 mutants show defects in male sporogenesis.
cancer and ageing
There’s a special issue in the journal Mechanisms of Ageing and Development devoted to cancer and ageing.
Below is the intro from the editors:
“An understanding of the relationship between aging and cancer is of more than mere academic interest. Biomedical research aims to intervene to prevent both. However, if the hypothesis that some aspects of the aging process itself evolved to suppress cancer is true, how will it be possible to restrain both aging and cancer?
This intellectual conundrum is intensified by the belief that cells need time to accumulate sufficient mutations for carcinogenesis to occur. Chronological time is, of course, the same for short and long-lived animals, so why is cancer a major cause of death of short-lived species like mice, as well as long-lived species such as humans (in protected environments in which death from external hazards is rare)? It seems that cancer incidence rates are governed not by chronological time but by processes that determine lifespan, at least in mammals. Thus, cancer incidence begins to rise at about the midpoint of the life span for most mammalian species. There must therefore be other explanations for why cancer rates (for most types of cancer) increase with age in both short- and longlived animals.”
RecQ and recombination-based DNA repair
Dharmendra Kumar Singh and colleagues wrote an article in the Biogerontology journal presenting the various roles of human RecQ helicases in recombination-based DNA repair. The physiological consequences of RecQ defects in the development of cancer and premature aging were also highlighted.
Fig. 4 RecQ helicases are involved in multiple steps of major recombination pathways. The members of the RecQ helicase family interacts with various proteins involved in different steps of the major recombination pathways i.e., error free homologous recombination (HR) pathway and error prone non-homologous end-joining (NHEJ) pathway.
Singh DK, Ahn B, Bohr VA. 2008. Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology. Dec 15. [Epub ahead of print]
Here’s one part about the WRN exonuclease:
“… it has been shown that WRN physically and functionally interacts with the major NHEJ factor XRCC4-DNA ligase IV complex (X4L4) which stimulates WRN exonuclease activity but not WRN helicase activity. Further, X4L4 is able to ligate a substrate processed by WRN exonuclease, suggesting the functional importance of this interaction (Kusumoto et al. 2008).”
Kusumoto R, Dawut L, Marchetti C, Wan Lee J, Vindigni A, Ramsden D, Bohr VA. 2008. Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing. Biochemistry 47:7548–7556. doi:10.1021/bi702325t
changes in The EMBO Journal
The EMBO Journal implements new intiatives for 2009. It will follow a transparent editorial process for a more constructive referee and author argumentation. In addition, citing primary literature is being encouraged whenever possible. References are now excluded from the character limit and from any page charges, authors can now freely cite all the papers they need to cite. And, a new heading ‘Have you seen…?’ will cover short, invited commentaries from scientists in the field on key articles. As another way of highlighting content, occasional Focus Issues will continue to pe assembled (reviews designed to bring together different fields around an idea, or illuminate them from a new angle).
rDNA variation
Lawrence Weider and colleagues wrote a review in 2005 covering ribosomal DNA variation. They discussed the interaction between rDNA and growth rate. They also highlighted the role of selection on rDNA variants in the microevolutionary process. They concluded that using biological stoichiometry to examine how evolutionary forces operate on rDNA variation can have a major effect on ecological interactions, via the ribosome biogenesis.
Here’s a portion of it (LV = length variant of the intergenic spacer IGS):
“Among the few animal studies that have utilized artificial selection on specific traits (e.g., growth rate, life-history traits) and examined concomitant changes in rDNA, the studies by Cluster et al. (1987) and Grimaldi & Di Nocera (1988) on D. melanogaster are noteworthy because they show a clear response of the rDNA to directional selection. Cluster et al. (1987) selected for fast and slow development times among lines of D. melanogaster and noted a significant shift in the frequency of IGS LVs in the two selection regimes. A greater proportion of the faster developing lines maintained longer LVs, whereas the slower developing lines maintained shorter LVs. Subsequent work by Grimaldi & Di Nocera (1988) showed that the rate of transcriptional production of pre-rRNA was directly proportional to the number of enhancers located in the IGS. These two studies provide support for the notion that genotypes composed of longer IGS LVs may benefit from higher rDNA transcriptional rates via more enhancer and promoter sites in the subrepeat region of the IGS and thus exhibit faster development (higher growth rates).”
perdurance
In 1971, Antonio Garcia-Bellido and John Merriam introduced the concept of perdurance to describe the persistence of a gene’s product after the removal of a gene from a cell. For example, if by mitotic exchange a m/m cell is made from a m/m+ progenitor, how long does the product of the wild-type allele m+ persist as the clone of m/m cells expands?
