Francesca Gorini

Genome stability is safeguarded by a finely orchestrated cascade of events that collectively represent the DNA damage response (DDR). In eukaryotes, the DDR operates within the dynamic chromatin landscape, where the interplay between DNA repair factors, chromatin remodeling, replication, transcription, spatial genome organization, and cytoskeletal forces is tightly coordinated. High-resolution studies have unveiled chromatin alterations spanning multiple scales, from localized kilobase-level changes to megabase-scale reorganization, which impact chromatin’s physical properties and enhance the mobility of damaged regions. Leveraging this knowledge could pave the way for innovative therapeutic strategies, particularly in targeting chromatin dynamics to destabilize cancer cells selectively. This review, focusing on DNA double-strand breaks (DSBs), sheds light on how chromatin undergoes dynamic modifications in response to damage and how these changes influence the DDR at both local and global levels, offering a glimpse into how nuclear architecture contributes to the delicate balance between genome stability and adaptability and highlighting the importance of exploring these interactions in the context of cancer therapy.

The guanine base in nucleic acids is, among the other bases, the most susceptible to being converted into 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) when exposed to reactive oxygen species. In double-helix DNA, 8-oxodG can pair with adenine; hence, it may cause a G > T (C > A) mutation; it is frequently referred to as a form of DNA damage and promptly corrected by DNA repair mechanisms. Moreover, 8-oxodG has recently been redefined as an epigenetic factor that impacts transcriptional regulatory elements and other epigenetic modifications. It has been proposed that 8-oxodG exerts epigenetic control through interplay with the G-quadruplex (G4), a non-canonical DNA structure, in transcription regulatory regions. In this review, we focused on the epigenetic roles of 8-oxodG and the G4 and explored their interplay at the genomic level.

Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA.