Is DNA damage response ready for action anywhere?

Abstract

Organisms are continuously exposed to DNA damaging agents, consequently, cells have developed an intricate system known as the DNA damage response (DDR) in order to detect and repair DNA lesions. This response has to be rapid and accurate in order to keep genome integrity. It has been observed that the condensation state of chromatin hinders a proper DDR. However, the condensation state of chromatin is not the only barrier to DDR. In this review, we have collected data regarding the presence of DDR factors on micronuclear DNA lesions that indicate that micronuclei are almost incapable of generating an effective DDR because of defects in their nuclear envelope. Finally, considering the recent observations about the reincorporation of micronuclei to the main bulk of chromosomes, we suggest that, under certain circumstances, micronuclei carrying DNA damage might be a source of chromosome instability.

Keywords: DSB repair; NER pathway; chromosome instability; micronuclei.

Figure 1

Model for nucleotide excision repair pathway including both subpathways: the global genomic repair (GGR) (left) and the transcription-coupled repair (TCR) (right).

Figure 2

Model relating the structure and functionality of the nuclear envelope to the import of XPC (Xeroderma pigmentosum group C) into the micronucleus: Diagram of the structure of the micronuclear envelope (left); Double nuclear pore complexes (NPC)/XPC immunofluorescence carried out in our laboratory (right). (A) Micronucleus with a proper envelope labeled with both NPC and XPC. (B) Micronucleus with dysfunctional NPCs labeled with NPC but it does not show XPC labeling. (C) Micronucleus lacking NPCs and, in some cases, without lamina as it does not display either NPC nor XPC.

Figure 3

Once a whole-chromosome containing micronucleus is formed, it may accumulate significant DNA damage due to exposure to exogenous damage or due to defective DNA replication. As DDR is defective in micronuclei, the damage will remain unrepaired. As recently demonstrated, micronuclei can reincorporate to the main nucleus after nuclear envelope breakdown. Subsequently, the damaged chromosome may be a source for chromosome reorganizations under certain circumstances. For instance, if chromosomes with dysfunctional telomeres are present, during the next G1-phase, the non-homologous end joining (NHEJ) can join the micronucleus-derived damaged-chromatid with the one lacking telomeres leading to the formation of a dicentric chromatid. After DNA replication and once in mitosis, the dicentric chromosome may initiate breakage-fusion-bridge (BFB) cycles. Therefore, in this situation, micronuclei could be a source for chromosome instability as BFB cycles already are.