A predictive chromatin architecture nexus regulates transcription and DNA damage repair.

Abstract

Genomes are blueprints of life essential for an organism's survival, propagation, and evolutionary adaptation. Eukaryotic genomes comprise of DNA, core histones, and several other nonhistone proteins, packaged into chromatin in the tiny confines of nucleus. Chromatin structural organization restricts transcription factors to access DNA, permitting binding only after specific chromatin remodeling events. The fundamental processes in living cells, including transcription, replication, repair, and recombination, are thus regulated by chromatin structure through ATP-dependent remodeling, histone variant incorporation, and various covalent histone modifications including phosphorylation, acetylation, and ubiquitination. These modifications, particularly involving histone variant H2AX, furthermore play crucial roles in DNA damage responses by enabling repair protein's access to damaged DNA. Chromatin also stabilizes the genome by regulating DNA repair mechanisms while suppressing damage from endogenous and exogenous sources. Environmental factors such as ionizing radiations induce DNA damage, and if repair is compromised, can lead to chromosomal abnormalities and gene amplifications as observed in several tumor types. Consequently, chromatin architecture controls the genome fidelity and activity: it orchestrates correct gene expression, genomic integrity, DNA repair, transcription, replication, and recombination. This review considers connecting chromatin organization to functional outcomes impacting transcription, DNA repair and genomic integrity as an emerging grand challenge for predictive molecular cell biology.