A role of the 53BP1 protein in genome protection: structural and functional characteristics of 53BP1-dependent DNA repair

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.

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades

“…2 We show that several biomarkers associated with photoexposure are increased in arm sites, including the cis/trans -urocanic acid ratio, foci of the DNA damage response marker 53BP1 that is sensitive to UV exposure, and epigenetic age derived from methylation levels of DNA an indicator of epigenetic aging. 11, 31–33 These methylation patterns are similar to what has been previously reported where the biopsies were enzymatically separated into epidermis and dermis fractions in contrast to LCM in our study. 34 Overall, this supports that the photoexposed arms undergo photodamage.…”

A Paradigm Revolution or Just Better Resolution—Will Newly Emerging Superresolution Techniques Identify Chromatin Architecture as a Key Factor in Radiation-Induced DNA Damage and Repair Regulation?

“…In addition, 53BP1 enhances repair fidelity independent of the repair pathway [150]. Hence, 53BP1 and some other proteins, such as BRCA1, probably establish structural platforms that support the recruitment and assembly of the repair machinery in specific ways, dictated by integrated information from multiple global and local factors (reviewed in [151]). Strikingly, 53BP1 and RIF1 were only recently discovered to form an autonomous functional module that stabilizes three-dimensional chromatin topology at sites of DNA breakage [150].…”

The FANC/BRCA Pathway Releases Replication Blockades by Eliminating DNA Interstrand Cross-Links

“…Several factors determine pathway choice, including cell cycle phase (in G1, only the NHEJ is effective), histone posttranslational modifications around the lesion and competition between the 53BP1 and BRCA1 proteins, which are the drivers of NHEJ and HRR, respectively. Indeed, 53BP1 aggregates on DSBs, protecting their extremities against nuclease-mediated resection, whereas BRCA1, driving nucleases such as CtIP, which extends the MRE11 resection, allowing DSB 3 -overhang formation [161]. However, during ICL repair, when a replication fork stalls and collapses, only a one-ended DSB is introduced.…”