Impact of DNA Mismatches on Nucleosome Stability

מושגי ליבה

The author explores how DNA mismatches influence nucleosome mechanical stability and accessibility, shedding light on genetic variations and potential implications for evolution and cancer progression.

תקציר

The content delves into the impact of DNA mismatches on nucleosome stability, revealing insights into how these mismatches affect genetic variation, nucleosome unwrapping dynamics, and DNA bendability. The study highlights the role of C-C mismatches in enhancing nucleosome mechanical stability and reducing nucleosomal DNA accessibility. Additionally, comparisons between yeast and Xenopus nucleosomes show differences in stability under tension.

סטטיסטיקה

A single base-pair C-C mismatch enhances DNA bendability and nucleosome mechanical stability.
Yeast nucleosomes are mechanically less stable compared to Xenopus nucleosomes.
The rate of genetic variation along the genome is correlated with nucleosome positions.
The increase in force required for DNA unwrapping from the histone core is observed for single base-pair C-C mismatches.
Adding a C-C mismatch reduces looping time dramatically, indicating increased DNA flexibility.

ציטוטים

"The results support a model where nucleosomal DNA accessibility is reduced by mismatches."
"Enhanced mechanical stability might shield DNA from transcription."
"A defect making the system more stable may appear counterintuitive."

תובנות מפתח מזוקקות מ:

Dependence of Nucleosome Mechanical Stability on DNA Mismatches

by Ngo,T. T. M.... ב- www.biorxiv.org 11-21-2022

https://www.biorxiv.org/content/10.1101/2022.11.21.517409v3

שאלות מעמיקות

How do species-specific differences in histones impact nucleosome stability?

In the study, it was observed that nucleosomes reconstituted with yeast histones exhibited slightly lower zero-force FRET values and were mechanically less stable compared to those reconstituted with Xenopus histones. Specifically, the outer turn of yeast nucleosomes unwrapped at a lower force than Xenopus nucleosomes, and the unwrapping pattern was less asymmetric for a significant portion of yeast nucleosomes formed on the 601 sequence. This suggests that species-specific differences in histones can influence nucleosome stability under tension. The variations in histone sequences and post-translational modifications may affect how DNA mechanics translate into nucleosome mechanics.

Could enhanced mechanical stability due to mismatches have broader implications beyond genetic variation?

The enhanced mechanical stability of nucleosomes resulting from mismatches could indeed have broader implications beyond genetic variation. One potential implication is that increased stability might shield DNA from transcription, preventing gene expression when misincorporated nucleotides are present. Additionally, the heightened mechanical stability could hinder access to repair machinery for mismatched sites within the DNA wrapped around the histone core. This reduced accessibility may lead to an accumulation of single-nucleotide polymorphisms near positioned nucleosomes, potentially serving as a mechanism for generating genetic diversity during evolution and contributing to cancer progression.

How can the findings about DNA flexibility be applied to understanding diseases like cancer?

Understanding DNA flexibility alterations caused by factors such as mismatches can provide valuable insights into diseases like cancer where genomic instability plays a crucial role. For instance:

DNA Repair Mechanisms: Changes in DNA flexibility due to mismatches can impact how efficiently repair mechanisms operate on damaged or mismatched sites within genes associated with cancer development.
Genomic Instability: Enhanced bendability induced by certain types of mismatches may contribute to increased genomic instability seen in cancers through altered chromatin structure or impaired repair processes.
Therapeutic Targets: Targeting pathways involved in regulating DNA flexibility or exploiting vulnerabilities arising from changes in chromatin dynamics related to mismatch-induced alterations could offer new avenues for therapeutic interventions targeting specific aspects of cancer biology.
Biomarkers: Assessing DNA flexibility profiles influenced by various factors including mismatches could serve as potential biomarkers for predicting susceptibility or prognosis related to certain types of cancers characterized by distinct patterns of genomic instability linked to altered chromatin structure and function.

These applications highlight how insights gained from studying DNA mechanics and its relationship with diseases like cancer can pave the way for novel diagnostic tools, treatment strategies, and deeper understandings of disease mechanisms at a molecular level.