Abstract
Nuclear architecture plays a significant role in DNA repair mechanisms. It is evident that proteins involved in DNA repair are compartmentalized in not only spontaneously occurring DNA lesions or ionizing radiation-induced foci (IRIF), but a specific clustering of these proteins can also be observed within the whole cell nucleus. For example, 53BP1-positive and BRCA1-positive DNA repair foci decorate chromocenters and can appear close to nuclear speckles. Both 53BP1 and BRCA1 are well-described factors that play an essential role in double-strand break (DSB) repair. These proteins are members of two protein complexes: 53BP1-RIF1-PTIP and BRCA1-CtIP, which make a “decision” determining whether canonical nonhomologous end joining (NHEJ) or homology-directed repair (HDR) is activated. It is generally accepted that 53BP1 mediates the NHEJ mechanism, while HDR is activated via a BRCA1-dependent signaling pathway. Interestingly, the 53BP1 protein appears relatively quickly at DSB sites, while BRCA1 is functional at later stages of DNA repair, as soon as the Mre11-Rad50-Nbs1 complex is recruited to the DNA lesions. A function of the 53BP1 protein is also linked to a specific histone signature, including phosphorylation of histone H2AX (γH2AX) or methylation of histone H4 at the lysine 20 position (H4K20me); therefore, we also discuss an epigenetic landscape of 53BP1-positive DNA lesions.
Highlights
Cells have evolved multiple conserved mechanisms for maintaining genome integrity, which is collectively termed the DNA damage response (DDR)
Tang et al [100] confirmed that H4K16 acetylation affects the binding of the 53BP1 protein to H4K20 dimethylated chromatin containing DNA lesions. Consistent with this observation, Miller et al [99] showed that histone deacetylase (HDAC) 1 and histone deacetylase 2 (HDAC 2) are responsible for H3K56 deacetylation, and these enzymes are recruited to double‐strand break (DSB) sites, whereas inhibition of histone deacetylase 1 (HDAC 1) and HDAC 2 reduces the accumulation of the 53BP1 protein at DNA lesions
We show that H4K20me2/me3 are dispersed within accumulated and robust 53BP1-positive DNA lesions, and these histone posttranslational modifications appear in close proximity to DSB sites [4]
Summary
Cells have evolved multiple conserved mechanisms for maintaining genome integrity, which is collectively termed the DNA damage response (DDR).
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