Tandem DNA repeats derived from the ancestral (TTAGGG)n run were first detected at chromosome ends of the majority of living organisms, hence the name telomeric DNA repeats. Subsequently, it has become clear that telomeric motifs are also present within chromosomes, and they were suitably called interstitial telomeric sequences (ITSs). It is well known that telomeric DNA repeats play a key role in chromosome stability, preventing end-to-end fusions and precluding the recurrent DNA loss during replication. Recent data suggest that ITSs are also important genomic elements as they confer its karyotype plasticity. In fact, ITSs appeared to be among the most unstable microsatellite sequences as they are highly length polymorphic and can trigger chromosomal fragility and gross chromosomal rearrangements. Importantly, mechanisms responsible for their instability appear to be similar to the mechanisms that maintain the length of genuine telomeres. This review compares the mechanisms of maintenance and dynamic properties of telomeric repeats and ITSs and discusses the implications of these dynamics on genome stability.

Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are nonrandomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability, including terminal inversions (recombination between the ITS and the “true” chromosome telomere) and point mutations in DNA sequences adjacent to the ITS. In the current study, we examine the genetic control of these events. We show that the terminal inversions occur by the single-strand annealing pathway of DNA repair following the formation of a double-stranded DNA break within the ITS. The point mutations induced by the ITS require the error-prone DNA polymerase ζ. Unlike the terminal inversions, these events are not initiated by a double-stranded DNA break, but likely result from the error-prone repair of a single-stranded DNA gap or recruitment of DNA polymerase ζ in the absence of DNA damage.

The yeast S. cerevisiae is a unique genetic object for which a wide range of relatively simple, inexpensive, and non-time-consuming methods have been developed that allow the performing of a wide variety of genome modifications. Among the latter, one can mention point mutations, disruptions and deletions of particular genes and regions of chromosomes, insertion of cassettes for the expression of heterologous genes, targeted chromosomal rearrangements such as translocations and inversions, directed changes in the karyotype (loss or duplication of particular chromosomes, changes in the level of ploidy), mating-type changes, etc. Classical yeast genome manipulations have been advanced with CRISPR/Cas9 technology in recent years that allow for the generation of multiple simultaneous changes in the yeast genome. In this review we discuss practical applications of both the classical yeast genome modification methods as well as CRISPR/Cas9 technology. In addition, we review methods for ploidy changes, including aneuploid generation, methods for mating type switching and directed DSB. Combined with a description of useful selective markers and transformation techniques, this work represents a nearly complete guide to yeast genome modification.

COVID-19 caused by the SARS-CoV-2 virus is a new type of infection which has caused an enormous social and economic burden across the world. While most people will develop a mild-to-moderate form of the disease or even stay asymptomatic, a certain proportion will get critically ill. COVID-19 mortality risk is higher in elderly patients and in patients with cardiovascular diseases and diabetes. Molecular mechanisms which underlie these risks are not yet understood for COVID-19. Here I discuss a possible association of COVID-19 complications with von Willebrand factor (VWF) level and endothelial damage. VFW is an important prognostic marker of endothelial dysfunction and its level fluctuates depending on age. VWF level is also variable depending on sex and race. Importantly, chloroquine, a drug that showed potential efficacy for COVID-19 treatment, can influence VWF secretion and consequently its level and activity. I propose that VWF level and activity might be predictors of the COVID-19 morbidity and mortality; moreover the VWF might be involved in the pathogenesis of the disease. I suggest that a comprehensive study of VWF level in SARS-CoV-2 positive groups of people with mild and severe course of the disease should be undertaken.

SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 variants differ in transmissibility and pathogenicity in the human population, although the molecular basis for this difference is still debatable. A significant role is attributed to amino acid changes in the binding surface of the Spike protein to the ACE2 receptor, which may facilitate virus entry into the cell or contribute to immune evasion. We modeled in silico the interaction between Spike RBDs of Wuhan-Hu-1, Delta, and Omicron BA.1 variants and ACE2 at different pHs (pH 5 and pH 7) and showed that the strength of this interaction was higher for the Omicron BA.1 RBD compared to Wuhan-Hu-1 or Delta RBDs and that the effect was more profound at pH 5. This finding is strikingly related to the increased ability of Omicron variants to spread in the population. We also noted that during its spread in the population, SARS-CoV-2 evolved to a more charged, basic composition. We hypothesize that the more basic surface of the Omicron variant may facilitate its spread in the upper respiratory tract but not in the lower respiratory tract, where pH estimates are different. We calculated the amyloidogenic properties of Spike RBDs in different SARS-CoV-2 variants and found eight amyloidogenic regions in the Spike RBDs for each of the variants predicted by the FoldAmyloid program. Although all eight regions were almost identical in the Wuhan to Gamma variants, two of them were significantly longer in both Omicron variants, making the Omicron RBD more amyloidogenic. We discuss how the increased predicted amyloidogenicity of the Omicron variants RBDs may be important for protein stability, influence its interaction with ACE2 and contribute to immune evasion.