BioEssays最新文献

The relationship of embryonal carcinoma (EC) cells, the stem cells of germ cell- or embryo-derived teratocarcinoma tumors, to early embryonic cells came under intense scrutiny in the early 1970s when mouse chimeras were produced between EC cells and embryos. These chimeras raised tantalizing possibilities and high hopes for different areas of research. The normalization of EC cells by the embryo lent validity to their use as in vitro models for embryogenesis and indicated that they might reveal information about the relationship between malignancy and differentiation. Chimeras also showed the way for the potential introduction of genes, selected in EC cells in vitro, into the germ line of mice. Although EC cells provided material for the elucidation of early embryonic events and stimulated many studies of early molecular differentiation, after years of intense scrutiny, they fell short as the means of genetic manipulation of the germ line, although arguably they pointed the way to the development of embryonic stem (ES) cells that eventually fulfilled this goal.

Precise DNA replication is fundamental for genetic inheritance. In eukaryotes, replication initiates at multiple origins that are first “licensed” and subsequently “fired” to activate DNA synthesis. Despite the success in identifying origins with specific DNA motifs in Saccharomyces cerevisiae, no consensus sequence or sequences with a predictive value of replication origins have been recognized in metazoan genomes. Rather, epigenetic rules and chromatin structures are believed to play important roles in governing the selection and activation of replication origins. We propose that replication initiation is facilitated by a group of sequence-specific “replication pioneer factors,” which function to increase chromatin accessibility and foster a chromatin environment that is conducive to the loading of the prereplication complex. Dysregulation of the function of these factors may lead to gene duplication, genomic instability, and ultimately the occurrence of pathological conditions such as cancer.

Ovarian cancer is the most lethal gynecological malignancy and is often associated with both DNA repair deficiency and extensive metabolic reprogramming. While still emerging, the interplay between these pathways can affect ovarian cancer phenotypes, including therapeutic resistance to the DNA damaging agents that are standard-of-care for this tumor type. In this review, we will discuss what is currently known about cellular metabolic rewiring in ovarian cancer that may impact DNA damage and repair in addition to highlighting how specific DNA repair proteins also promote metabolic changes. We will also discuss relevant data from other cancers that could be used to inform ovarian cancer therapeutic strategies. Changes in the choice of DNA repair mechanism adopted by ovarian cancer are a major factor in promoting therapeutic resistance. Therefore, the impact of metabolic reprogramming on DNA repair mechanisms in ovarian cancer has major clinical implications for targeted combination therapies for the treatment of this devastating disease.

Most people know that using the word “sex” in a title will get you many more “clicks.” So, now that you are here, how do I hold your attention? By doing two things: (i) tell you about one of the most beautiful scientific articles I ever encountered, and (ii) explain how the process of eukaryotic “meiotic” sex illustrates exquisitely that biology can only be understood as the interplay of historical accident and physio-chemical constraints. I will start with (ii). Though the studies about meiotic sex fill libraries, most researchers focus on just a few basic, interrelated, questions: Why settle for only giving half your genome to a new generation (if lucky enough to be able to) instead of just cloning yourself?; How did this elaborate, complex, process evolve and under which selective pressures?; How do selective forces during its origins relate to present-day advantages (if any)?

Thus, simply put: Meiotic sex, what is it good for? To present just a few answers: (i) The Red Queen “arms race” model, stating that as species (constituting prey, predator, host, and pathogen) are constantly pitted against other rapidly evolving opposing species, they have to change quickly, and only sex enables this^[1]; (ii) The first model can be seen as a specific instance of a more general framework: recombination, implicit in meiotic sex, allows a much faster probing of the space of combinatorial possibilities: selecting winners and weeding out losers^[2]; (iii) Overcoming the limitations imposed by Muller's Ratchet: the process leading to accumulated, irreversible, deleterious mutations. Absent purifying sexual recombination, only organisms combining small genomes and low mutational loads can survive. Thus, without meiotic sex, the larger genomes of eukaryotes would be unsustainable.

Here we come to the crucial insight illustrating the interaction of historical accidents and nature's laws in biology. All the hypotheses mentioned explain the possible advantages, but as evolution has no foresight, only the last framework can be used to explain the emergence of meiotic sex and its presence in the last eukaryotic common ancestor, because it invokes direct adaptation to actual selection forces, instead of later advantages. Many researchers now accept that eukaryotes emerged from the merger of an (Asgard) archaeon and an alpha-proteobacterial endosymbiont, capable of oxidative respiration, which would become the mitochondrion.^[3] Thus, the evolving organism would have had to contend with an initial genome doubling in size and (much) higher mutation rates because of internal reactive oxygen species (ROS) formation. Considering Muller's Ratchet: a deadly combination. Archaeal genome repair mechanisms evolved into full blown meiotic sex next.^[4]