The eukaryotic genome can be roughly divided into euchromatin and heterochromatin domains that are structurally and functionally distinct. Heterochromatin is characterized by its high compaction that impedes DNA transactions such as gene transcription, replication, or recombination. Beyond its role in regulating DNA accessibility, heterochromatin plays essential roles in nuclear architecture, chromosome segregation, and genome stability. The formation of heterochromatin involves special histone modifications and the recruitment and spreading of silencing complexes that impact the higher-order structures of chromatin; however, its molecular nature varies between different chromosomal regions and between species. Although heterochromatin has been extensively characterized, its formation and maintenance throughout the cell cycle are not yet fully understood. The biggest challenge for the faithful transmission of chromatin domains is the destabilization of chromatin structures followed by their reassembly on a novel DNA template during genomic replication. This destabilizing event also provides a window of opportunity for the de novo establishment of heterochromatin. In recent years, it has become clear that different types of obstacles such as tight protein-DNA complexes, highly transcribed genes, and secondary DNA structures could impede the normal progression of the replisome and thus have the potential to endanger the integrity of the genome. Multiple studies carried out in different model organisms have demonstrated the capacity of such replisome impediments to favor the formation of heterochromatin. Our review summarizes these reports and discusses the potential role of replication stress in the formation and maintenance of heterochromatin and the role that silencing proteins could play at sites where the integrity of the genome is compromised.

Base excision repair (BER) removes DNA damage induced by endogenous reactive oxygen species or ionizing radiation, important breast cancer risk factors. Genetic variation associated with impaired BER might thus increase breast cancer risk. Therefore, we assessed risk associations of 123 common single nucleotide polymorphisms (SNPs) in 19 BER genes in 1,639 postmenopausal breast cancer cases and 1,967 controls from the German population-based case-control study MARIE. SNPs were tagging SNPs representing genetic variation across the gene together with potentially functional SNPs. Risk associations were assessed using conditional logistic regression, adjusted for potential breast cancer risk factors. Significant associations between polymorphisms and breast cancer risk were found for one SNP in PARP2 and three SNPs in the mitochondrial DNA polymerase gamma, POLG. A SNP in the promoter region of POLG (rs2856268, A>G) showed a protective effect for homozygous GG carriers (odds ratio 0.81, 95% confidence intervals 0.65-1.00). Joint analysis of an enlarged sample set and haplotype analysis supported the results for POLG. Quantification of POLG mRNA expression in lymphocytes of 148 breast cancer patients revealed higher mRNA levels for rs2856268 GG carriers (p value 5 0.038). A luciferase promoter assay showed significant differences between constructs harboring the respective alleles. Taken together, our results suggest that genetic variation in the POLG promoter region affects DNA polymerase gamma levels in mitochondria. This could contribute to the reported increase in mitochondrial mutation frequency resulting in dysfunction and altered breast cancer risk. Risk effects and the functional impact of the POLG promoter variant require further confirmation.Numerous risk factors like family history of the disease or hormone replacement therapy are known to contribute to breast cancer development, the most frequent cancer type in women. 1 In addition, oxidative stress is discussed to be involved. Reactive oxygen species (ROS) can originate from endogenous and exogenous processes, e.g., from cellular estrogen metabolism and exposure to tobacco smoke or ionizing radiation. [2][3][4] Normally, the amount of cellular ROS is well balanced between proteins producing and scavenging oxidative species, but this homeostasis can be disrupted under certain conditions. Then, oxidative DNA damage will occur, which, if not repaired, can cause mutations and genomic instability. 5 Insufficient DNA repair is one of the prominent risk factors for breast cancer. 6 The hereditary, high penetrance mutations in BRCA1 or 2 genes strongly increase the risk by disrupting DNA double strand break repair. But also, genetic variation by single nucleotide polymorphisms (SNPs) in further DNA repair genes has been suggested to play an important role. 7,8 Regarding the repair of oxidative damage, mainly base excision repair (BER) is involved. This pathway consists of about 11 damage specific DNA glycosylases and further proteins which tightly cooperate. 9-...