16 research outputs found
Simultaneous disruption of two DNA polymerases, Polη and Polζ, in Avian DT40 cells unmasks the role of Polη in cellular response to various DNA lesions
Replicative DNA polymerases are frequently stalled by DNA lesions. The resulting replication blockage is released by homologous recombination (HR) and translesion DNA synthesis (TLS). TLS employs specialized TLS polymerases to bypass DNA lesions. We provide striking in vivo evidence of the cooperation between DNA polymerase η, which is mutated in the variant form of the cancer predisposition disorder xeroderma pigmentosum (XP-V), and DNA polymerase ζ by generating POLη−/−/POLζ−/− cells from the chicken DT40 cell line. POLζ−/− cells are hypersensitive to a very wide range of DNA damaging agents, whereas XP-V cells exhibit moderate sensitivity to ultraviolet light (UV) only in the presence of caffeine treatment and exhibit no significant sensitivity to any other damaging agents. It is therefore widely believed that Polη plays a very specific role in cellular tolerance to UV-induced DNA damage. The evidence we present challenges this assumption. The phenotypic analysis of POLη−/−/POLζ−/− cells shows that, unexpectedly, the loss of Polη significantly rescued all mutant phenotypes of POLζ−/− cells and results in the restoration of the DNA damage tolerance by a backup pathway including HR. Taken together, Polη contributes to a much wide range of TLS events than had been predicted by the phenotype of XP-V cells
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Phyloepidemiological analysis reveals that viral divergence led to the paucity of SIVmus/gsn/mon infections in wild populations
Human immunodeficiency virus subtype-1 (HIV-1) is the result of cross-species transmission of simian immunodeficiency virus from chimpanzees (SIVcpz). SIVcpz is a chimeric virus which shares common ancestors with viruses infecting red capped mangabeys and a subset of guenon species. The epidemiology of SIV infection in hominoids is characterized by low prevalence and uneven geographical distribution. Surveys in Cameroon indicated that two closely related members of the guenon species subset, mustached guenons and greater spot-nosed guenons, infected with SIVmus and SIVgsn respectively, have also low rates of SIV infections in their populations. Compared to other monkeys, including red capped mangabeys and closely related guenon species, such an epidemiology is unusual.By intensifying sampling of geographically distinct populations of moustached and greater spot-nosed guenons in Gabon, and including large sample sets of mona guenons in Cameroon, we add strong support that the paucity of SIV infections in wild populations is a general feature of this monophyletic group of viruses. Furthermore, comparative phylogenetic analysis reveals that this phenotype is a feature of this group of viruses infecting phylogenetically dispirate hosts, suggesting that this epidemiological phenotype results from infection with these HIV-1 related viruses rather than a common host factor. Thus, these HIV-1 related viruses, SIVcpz and the guenon viruses which share a common ancestor with part of the SIVcpz genome, have a distinct epidemiology to that found in other African primate species.
: Stable virus-host relationships are established over multiple generations. The prevalence of viral infections in any given host is determined by various factors. Stable virus-host relationships of viruses that are able to cause persistent infections and exist with high incidences of viral infections are generally characterized by a lack of morbidity prior to host reproduction. Such is the case for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection in humans.SIV infections of most African primate species also satisfy these criteria, being found at a high prevalence, with rare cases of clinical disease. By contrast, SIVcpz, the ancestor of HIV-1 infection in humans, has a different epidemiology and it has been reported that these animals suffer from an AIDS-like disease in the wild. Here we conclusively demonstrate that viruses which are closely related to SIVcpz and infect a subset of guenon monkeys show an epidemiology resembling that of chimpanzees
PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2
10.1038/nm.2122Nature Medicine165580-58