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Researchers used advanced microscopy techniques to investigate how chromatin structure changes at the nanoscale when DNA double-strand breaks occur. Studying metaphase chromosomes from cells treated with the chemotherapeutic agent bleomycin, they found that DNA damage triggers protein structural changes indicating repair protein recruitment, alterations in DNA condensation patterns, and global DNA demethylation converting 5-methylcytosine to 5-hydroxymethylcytosine. These molecular changes correlate with chromatin relaxation that enhances accessibility for DNA repair machinery.
Why it matters
Understanding how chromatin reorganizes during DNA damage response could improve cancer treatments that rely on damaging tumor cell DNA, and may inform development of therapies that enhance or inhibit DNA repair processes. The nanoscale mapping approach provides insights into fundamental cellular mechanisms that protect genomic stability.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
DNA Double Strand Breaks (DSBs) threaten genomic stability, leading to cell death, chromosomal rearrangements, and cancer-driving mutations. Therefore, the effective repair mechanisms are essential for maintaining genomic stability and ensuring cellular survival across diverse organisms. At the core of this process lies chromatin integrity, which facilitates the local DNA conformational changes, regulating accessibility to repair proteins and other biomolecules. To deepen our understanding of the DNA damage response pathway, the local molecular mechanisms regulating the interplay between DNA damage formation and alterations in chromatin conformation must be investigated at the nanoscale level. Here, we integrated atomic force microscope-infrared spectroscopy (AFM-IR) and confocal fluorescence microscopy to explore local chemical modifications in DNA structure and chromatin integrity in metaphase chromosomes and chromosomal aberrations isolated from cells treated with the chemotherapeutic agent, bleomycin. Our findings reveal changes in secondary protein structures, indicating the engagement of DNA repair proteins with high {beta}-sheet content. Nanospectroscopic mapping resolved the alterations in DNA condensation along the chromosomes. Moreover, we observed global DNA demethylation, particularly the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), correlating with increased DSBs. We conclude that these transitions in protein conformation and DNA methylation correlate with chromatin relaxation and enhanced accessibility for the repair protein.
Source: Nanoscale insights into chromatin integrity molecular rearrangements upon DNA damage response