In the light of recent data, a way is described between mutations in TAD anchors and stimulation of tumor growth driven by chromosome instability. At the end of this way every tumor sacrifices by a portion of its cells, dying necrotically, to stimulate remaining cells to proliferate. Necrosis (cell puncture and leakage of chemokine CXCL12) launches the mechanism of wound healing that stimulates cells to divide. Necrosis in cancer cells is induced by chromosome aberrations hindering anaphase cleavage furrow ingression and leading to membrane rupture. Inherited chromosome instability arises, because some of DNA loops (gene blocks, also called TADs) are torn off chromatid axes at their attachment points (anchors) because of mutations at some of these points. Namely, CTCF target sites (CCXXXAGGGGG) at the basements of TAD loops acquire mutations in central Adenine and in 3–5 nucleotides just beyond the borders of this 11 bp sequence. The sequence itself is degenerate between different TADs mainly at the X nucleotides, rarely at some others. Interstitial satellite DNA (SAT) adjacent to TADs anchors begins to behave such as telomeric satellite DNA. This launches transcription of such erupted satellites not leaned against TADs and production of their DNA copies due to the action of TERT reverse transcriptase just like in telomeres and leads to insertion of telomere sequences into such SATs. Some sticky ends in satellites also add to chromosome instability.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a serious global health problem that kills over 1 million people annually. Understanding the pathogenesis of TB and the emergence of drug-resistant strains of Mtb is a priority for the development of strategies against TB. Its DNA damage and repair systems are essential for maintaining genome stability in Mtb. Their aberrant work leads to hypermutability and is often associated with the emergence of resistant bacteria. On the other hand, Mtb infection also induces genome instability of host cells, which are involved in the pathogenesis of TB, including the formation of giant cells. Collectively, this review is an attempt to summarize our current understanding of the role of genome instability in the pathogenesis of TB and to shed light on the development of new strategies for TB treatment.

Next-generation sequencing (NGS) of single cells and micro-dissected tissues has demonstrated that the number of somatic mutations in normal cells increases linearly with age. The majority of somatic mutations are single base substitutions (SBSs). NGS has revealed the mutagenic effect of various metabolic and environmental genotoxic agents on different cells, such as normal colonic epithelial cells, hematopoietic cells, hepatocytes, and neurons. NGS has also uncovered the clonal expansion of cells in normal tissues of the elderly driven by oncogenic mutations. There are two main mechanisms for the generation of mutations, namely, replication errors and DNA damage, with both being followed by inaccurate repair. NGS studies of normal tissues highlight the substantial contribution of the latter mechanism by revealing the significant accumulation of somatic mutations in mitotically inactive hepatocytes and neurons. This review describes the nature of spontaneously arising SBSs in normal tissues, the causes of mutagenesis, cellular pathways of the DNA damage response that suppress mutagenesis, as well as unsolved questions on the matter.

The stem of Celastrus orbiculatus, a traditional Chinese herbal medicine exhibits prominent anti-inflammatory and anti-tumor activities. In the present study, we prepared terpenoids-enriched fraction termed TTC (Total Terpenoids of C. orbiculatus) and explored the potentials of TTC as a sensitizer of gemcitabine by targeting DNA damage response in treatment of pancreatic cancer. Initially, we characterized the chemical profile of TTC. TTC and constitutional terpenoids showed antitumor effects through prohibiting the proliferation of AsPC-1 and BxPC-3 cells using EdU incorporation assay. Next, we quantified the interaction between TTC and gemcitabine which produced synergistic effects under sub-IC₅₀ concentrations. Moreover, TTC could further block S-phase entry or induce higher extent of apoptosis in the presence of gemcitabine. Of note, we observed that TTC caused DNA breaks in two PC cells assayed by single cell gel electrophoresis and metaphase spreading. We also ruled out the oxidative damage of DNA upon TTC exposure. Mechanically, TTC abrogated Chk1/RAD51, promoted accumulation of γH2AX and reversed replication stress associated DNA damage response triggered by gemcitabine. TTC destabilized nuclear Chk1 and RAD51 loading via proteasomal degradation. Additionally, the ectopic expression of hotspot mutant p53 (R175H, R248W and R273H) in p53-null AsPC-1 cells displayed increased expression of RAD51, which could be compromised by TTC. In an orthotopic mouse model of mCherry-BxPC-3 cells, we confirmed the in vivo anti-metastatic efficacy of TTC in combination with gemcitabine. These data provide insight into how TTC and molecules involved in DNA damage and repair could be effectively multi-targeted and confer chemosensitivity to gemcitabine toward pancreatic cancer.