Fanconi anemia: at the Crossroads of DNA repair

Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA patients suffer developmental abnormalities, early-onset bone marrow failure, and a predisposition to cancer. The disease is manifested by defects in DNA repair, hypersensitivity to DNA crosslinking agents, and a high degree of chromosomal aberrations. The FA pathway comprises 13 disease-causing genes involved in maintaining genomic stability. The fast pace of study of the novel DNA damage network has led to the constant discovery of new FA-like genes involved in the pathway that when mutated lead to similar disorders. A majority of the FA proteins act as signal transducers and scaffolding proteins to employ other pathways to repair DNA. This review discusses what is known about the FA proteins and other recently linked FA-like proteins. The goal is to clarify how the proteins work together to carry out interstrand crosslink repair and homologous recombination-mediated repair of damaged DNA.     

Cooperation and Defection at the Crossroads

We study a simple traffic model with a non-signalized road intersection. In this model the car arriving from the right has precedence. The vehicle dynamics far from the crossing are governed by the rules introduced by Nagel and Paczuski, which define how drivers behave when braking or accelerating. We measure the average velocity of the ensemble of cars and its flow as a function of the density of cars on the roadway. An additional set of rules is defined to describe the dynamics at the intersection assuming a fraction of drivers that do not obey the rule of precedence. This problem is treated within a game-theory framework, where the drivers that obey the rule are cooperators and those who ignore it are defectors. We study the consequences of these behaviors as a function of the fraction of cooperators and defectors. The results show that cooperation is the best strategy because it maximizes the flow of vehicles and minimizes the number of accidents. A rather paradoxical effect is observed: for any percentage of defectors the number of accidents is larger when the density of cars is low because of the higher average velocity.     

Emi2 at the Crossroads: Where CSF Meets MPF

Vertebrate eggs arrest at metaphase of meiosis II due to an activity known as cytostatic factor (CSF). CSF antagonizes the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C), preventing cyclin B destruction and meiotic exit until fertilization occurs. A puzzling feature of CSF arrest is that APC/C inhibition is leaky. Ongoing cyclin B synthesis is counterbalanced by a limited amount of APC/C-mediated cyclin B destruction; thus, cyclin B/Cdc2 activity remains at steady state. How the APC/C can be slightly active toward cyclin B, and yet restrained from ubiquitinating cyclin B altogether, is unknown. Emi2/XErp1 is the critical CSF component directly responsible for APC/C inhibition during CSF arrest. Fertilization triggers the Ca2+-dependent destruction of Emi2, releasing the APC/C to ubiquitinate the full pool of cyclin B and initiate completion of meiosis. Previously, we showed that a phosphatase maintains Emi2’s APC/C-inhibitory activity in CSF-arrested Xenopus egg extracts. Here, we demonstrate that phosphatase inhibition permits Emi2 phosphorylation at thr-545 and -551, which inactivates Emi2. Furthermore, we provide evidence that adding excess cyclin B to CSF extracts stimulates Cdc2 phosphorylation of these same residues, antagonizing Emi2-APC/C association. Our findings suggest a model wherein the pool of Emi2 acts analogously to a rheostat by integrating Cdc2 and phosphatase activities to prevent cyclin B overaccumulation and Cdc2 hyperactivity during the indefinite period of time between arrival at metaphase II and eventual fertilization. Finally, we propose that inactivation of Emi2 by Cdc2 permits mitotic progression during early embryonic cleavage cycles.     

Evolution at the Crossroads: Modern Human Emergence in Western Asia

There is long-standing disagreement regarding Upper Pleistocene human evolution in Western Asia, particularly the Levant. Some argue that there were two dilierent populations, perhaps different species, of Upper Pleistocene Levantine hominids. The first, from the Israeli silcs of Qafzeh and Skhul. is anatomically modern. The second, from sites such as Amud. Kcbara. and Tabun, is archaic, or "Neandertal" in morphology. Others argue that ihis is a false dichotomy and that all of lliese hominids belong to a single, highly variable population. In this paper I attempt to resolve this issue by examining posteranial measures reflective of body shape. Results indicate that the Qafzeh-Skhul hominids have African-like, or tropically adapted, proportions, while tliosc from Amud, Kebara. Tabun. and Shanidar (Iraq) have more European-like, or cold-adapled. proportions. This suggests that iherc were in fact two distinct Western Asian populations and that the Qaf/ch-Skhul hominids were likely African in origin—i result consistent with the "Replacement"' model of modern human origins, [modern human origins, NeunJertals, Qafzeh-Skhul hominids, body shape]