Abstract
The entire genome becomes mobilized following DNA damage. Understanding the mechanisms that act at the genome level requires that we embrace experimental and computational strategies to capture the behavior of the long-chain DNA polymer, which is the building block for the chromosome. Long-chain polymers exhibit constrained, sub-diffusive motion in the nucleus. Cross-linking proteins, including cohesin and condensin, have a disproportionate effect on genome organization in their ability to stabilize transient interactions. Cross-linking proteins can segregate the genome into sub-domains through polymer–polymer phase separation (PPPS) and can drive the formation of gene clusters through small changes in their binding kinetics. Principles from polymer physics provide a means to unravel the mysteries hidden in the chains of life.
Highlights
In the span of the last several years, the field has identified two distinct modes of the compartmentalization of genomic sub-domains. One of these is through liquid–liquid phase separation (LLPS), the other through polymer–polymer phase separation (PPPS) [23]
Using the nucleolus as a model, we have shown that the timescale of binding kinetics has a measurable impact on the segregation and heterogeneity of gene clusters within the nucleolus [17,36]
Polymer physics is a powerful guide for the behavior of a transient, responsive, crosslinked network such as the genome
Summary
Repair of DNA damage within heterochromatin [1,2], the nucleolus [3,4], and the centromere [5,6] are examples of compartments that contribute to repair pathway choice. Layered on these constraints is the motion of the DNA itself. Stochastic simulations of entropydriven, bead–spring polymer chain models account for many features of the dynamic properties of chromatin fibers, and have been responsible for significant advances in the past decade, elucidating higher-order genome organization. The challenge in the DNA damage and repair field is to marry the static DNA sequence-based perspective, the enzymology of DNA repair, and live cell measurements of DNA movement with the modeling of a dynamic bead–spring chromatin polymer
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