Katharina Schlacher

Bio: Katharina Schlacher is an academic researcher from University of Texas MD Anderson Cancer Center. The author has contributed to research in topics: DNA replication & DNA repair. The author has an hindex of 16, co-authored 31 publications receiving 2338 citations. Previous affiliations of Katharina Schlacher include Memorial Sloan Kettering Cancer Center & University of Southern California.

Lessons from 50 years of SOS DNA-damage-induced mutagenesis

Abstract: SOS mutagenesis is the 'mutation-prone' cellular replication mechanism that is responsible for UV-induced mutations. More than 50 years of SOS mutagenesis research has exposed the underlying mechanisms of DNA-damage-induced mutagenesis that combine the overlapping functions of replication, repair and recombination. This historical perspective integrates 50 years of research on SOS mutagenesis in Escherichia coli with the proverbial '3R' functions—replication, repair and recombination—that feature DNA polymerase V. Genetic and biochemical data are assimilated to arrive at a current picture of UV-damage-induced mutagenesis. An unprecedented DNA polymerase V transactivation mechanism, which involves the RecA protein, sheds new light on unresolved issues that have persisted over time, prompting us to reflect on evolving molecular concepts regarding DNA structures and polymerase-switching mechanisms.

RecA acts in trans to allow replication of damaged DNA by DNA polymerase V

Abstract: The DNA polymerase V (pol V) and RecA proteins are essential components of a mutagenic translesion synthesis pathway in Escherichia coli designed to cope with DNA damage. Previously, it has been assumed that RecA binds to the DNA template strand being copied. Here we show, however, that pol-V-catalysed translesion synthesis, in the presence or absence of the β-processivity-clamp, occurs only when RecA nucleoprotein filaments assemble or RecA protomers bind on separate single-stranded (ss)DNA molecules in trans. A 3′-proximal RecA filament end on trans DNA is essential for stimulation; however, synthesis is strengthened by further pol V–RecA interactions occurring elsewhere along a trans nucleoprotein filament. We suggest that trans-stimulation of pol V by RecA bound to ssDNA reflects a distinctive regulatory mechanism of mutation that resolves the paradox of RecA filaments assembled in cis on a damaged template strand obstructing translesion DNA synthesis despite the absolute requirement of RecA for SOS mutagenesis. A new model for the repair of damaged DNA in Escherichia coli could resolve earlier contradictory observations. Unrepaired DNA lesions can block genome replication, so the cell has defences to deal with such lesions when they are encountered by the replication machinery. In E. coli this involves pol V, a specialized DNA polymerase and RecA, a DNA repair protein. Previous work suggested that RecA binds to single-stranded DNA (ssDNA) on the same strand as the lesion, stimulating pol V to synthesize DNA across the damaged template. Now Schlacher et al. show that in fact RecA binds to a different ssDNA, and activates pol V 'in trans', not on the strand being copied.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Causes and consequences of replication stress.

Abstract: Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.

Microbiological effects of sublethal levels of antibiotics

Abstract: The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

BRCA1 and BRCA2: different roles in a common pathway of genome protection

Abstract: The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication.