A new study shows that the TLK1 and TLK2 enzymes are critical for ensuring the copying of DNA. The research is based on previous studies that pointed to TLK1/2 as potential candidate targets in cancer therapy, and it provides new molecular details on their key functions in cancer cell proliferation. (Mehr in: Cancer News — ScienceDaily)
Human cells divide and create new cells throughout life. In this process, a steady — even rhythmic — supply of DNA building blocks is needed to create new DNA. Now researchers have shown exactly how human cells regulate this process so it does not fail and cause illness. The researchers also show how they can manipulate the rhythm and suggest how this can be used in the future to kill cancer cells. (Mehr in: Cancer News — ScienceDaily)
Error surveillance and repair mechanisms during DNA replication do not show the same competence in all regions of the human genome. Scientists have discovered that the mechanism that repairs errors in DNA is more efficient in the regions of genes that hold information for the production of proteins. (Mehr in: Cancer News — ScienceDaily)
Problems with DNA replication can cause epigenetic changes that may be inherited for several generations
Scientists reveal that a fault in the process that copies DNA during cell division can cause epigenetic changes that may be inherited for up-to five generations. They also identified the cause of these epigenetic changes, which is related to the loss of a molecular mechanism in charge of silencing genes. Their results will change the way we think about the impact of replication stress in cancer and during embryonic development, as well as its inter-generational inheritance. (Mehr in: Cancer News — ScienceDaily)
A research team has solved the three-dimensional structure of a key protein that helps damaged cellular DNA repair itself. Investigators say that knowing the chemical structure of the protein will likely help drug designers build novel anti-cancer agents. (Mehr in: Cancer News — ScienceDaily)
Before a cell divides, it must first handle a large-scale project: Its entire genetic material has to be duplicated so that each of the two daughter cells is equipped with a full copy after cell division. As errors in this DNA replication could lead to the death of the cell, the process is rigorously controlled. It takes place in two phases. Researchers at the Max Planck Institute of Biochemistry in Martinsried have now revealed in the journal Cell Reports that these two phases are strictly separated from one another by breaks, thereby preventing errors in the DNA replication. (Mehr in: Pressemitteilungen – idw – Informationsdienst Wissenschaft)
A team of researchers has identified an enzyme that separates DNA replication from repair. This discovery could be of tremendous significance in the treatment of tumors. (Mehr in: Cancer News — ScienceDaily)
The genetic material of cancer cells is unstable. For example, the number of chromosomes, which are the individual elements of packed DNA, is changed in so called aneuploidies. This imbalance in chromosomes, which often occurs early in tumor development, leads to cell stress and promotes disease. How this can happen is now shown by the discovery of a research team led by Zuzana Storchová at the Max Planck Institute of Biochemistry in Martinsried, reported in a groundbreaking study published in Nature Communications. An imbalance in an enzyme called MCM2-7 that is essential for DNA replication is likely to be responsible for this escalating genomic instability. (Mehr in: Pressemitteilungen – idw – Informationsdienst Wissenschaft)
The cause of some cancers, including breast cancer and leukemia, is better understood, thanks to recent research. In the new study, the researchers found that too much of a key protein, called cyclin E, slows down DNA replication and introduces potentially harmful cancer-linked mutations when cells divide. (Mehr in: Cancer News — ScienceDaily)
Muhammad A Shah, Emily L Denton, Cheryl H Arrowsmith, Mathieu Lupien and Matthieu Schapira
The notion that epigenetic mechanisms may be central to cancer initiation and progression is supported by recent next-generation sequencing efforts revealing that genes involved in chromatin-mediated signaling are recurrently mutated in cancer patients.
Here, we analyze mutational and transcriptional profiles from TCGA and the ICGC across a collection 441 chromatin factors and histones. Chromatin factors essential for rapid replication are frequently overexpressed, and those that maintain genome stability frequently mutated. We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.
This unbiased approach confirms previously published data, uncovers novel cancer-associated aberrations targeting epigenetic mechanisms, and justifies continued monitoring of chromatin-related alterations as a class, as more cancer types and distinct cancer stages are represented in cancer genomics data repositories.
Tomasetti and Vogelstein show that the lifetime risk of cancers of many different types is strongly correlated with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to bad luck, that is, random mutations arising during DNA replication in normal, noncancerous stem cells.
Tomasetti C, Vogelstein B (2015): Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2 January 2015: Vol. 347 no. 6217 pp. 78-81 DOI: 10.1126/science.1260825
Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci
A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs).
We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an ‘autosomal Barr body’ with less compacted chromatin and incomplete RNAP II exclusion.
3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi.