Encounters in Three Dimensions: How Nuclear Topology Shapes Genome Integrity.

Robin Sebastian,Mirit I Aladjem,Philipp Oberdoerffer

doi:10.3389/fgene.2021.746380

Robin Sebastian, Mirit I Aladjem + Show 1 more

Open Access

https://doi.org/10.3389/fgene.2021.746380

Copy DOI

Abstract

Almost 25 years ago, the phosphorylation of a chromatin component, histone H2AX, was discovered as an integral part of the DNA damage response in eukaryotes. Much has been learned since then about the control of DNA repair in the context of chromatin. Recent technical and computational advances in imaging, biophysics and deep sequencing have led to unprecedented insight into nuclear organization, highlighting the impact of three-dimensional (3D) chromatin structure and nuclear topology on DNA repair. In this review, we will describe how DNA repair processes have adjusted to and in many cases adopted these organizational features to ensure accurate lesion repair. We focus on new findings that highlight the importance of chromatin context, topologically associated domains, phase separation and DNA break mobility for the establishment of repair-conducive nuclear environments. Finally, we address the consequences of aberrant 3D genome maintenance for genome instability and disease.

Highlights

Eukaryotic genomes are exposed to numerous sources of DNA damage, of which DNA doublestrand breaks (DSBs) are arguably the most deleterious
Defects in a given repair pathway or inappropriate repair pathway choice can be exploited for synthetic lethal cancer therapy approaches, such as Nuclear Topology Shapes Genome Integrity poly(ADP-ribose) polymerase 1 (PARP1) inhibition, which selectively kills HR-deficient cancers (Lord and Ashworth, 2017)
MMEJ, which like HR relies on the resection of broken DNA ends to expose patches of homology for break alignment and repair, was found to be more frequent in specialized heterochromatic chromatin environments marked by H3 trimethylated at K27 (H3K27me3) (Schep et al, 2021). These findings suggest that despite a common initial end processing step, HR and MMEJ are differentially controlled by chromatin context, perhaps by regulating the shift from short-range resection to long-range resection generally associated with HR (Symington and Gautier, 2011; Scully et al, 2019)

Summary

INTRODUCTION

Eukaryotic genomes are exposed to numerous sources of DNA damage, of which DNA doublestrand breaks (DSBs) are arguably the most deleterious. . .] PARP inhibitor resistance and chromosomal instability in cancer cells in cancer cells (Khurana et al, 2014; Karakashev et al, 2020) Together, these recent advances exemplify the impact of improved integrative analyses of chromatin composition on our understanding of genome maintenance. These recent advances exemplify the impact of improved integrative analyses of chromatin composition on our understanding of genome maintenance They further emphasize the need to i) consider functionally distinct proteoforms, often as the result of alternative splicing, and ii) distinguish lesion-specific from global effects of chromatin perturbation such as the epigenetic deregulation of repair factors

Chromatin Domains Guide DNA Replication

Movement and Clustering of DNA Lesions

Phase Separation in Neurodegenerative Disease