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Is DNA damage response ready for action anywhere?

Terradas M, Martín M, Hernández L, Tusell L, Genescà A - Int J Mol Sci (2012)

Bottom Line: This response has to be rapid and accurate in order to keep genome integrity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain; E-Mails: marta.martin@uab.cat (M.M.); laia.hernandez@uab.cat (L.H.); laura.tusell@uab.cat (L.T.); anna.genesca@uab.cat (A.G.).

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.

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Related in: MedlinePlus

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.
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f3-ijms-13-11569: 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.

Mentions: The collected data suggest that the DDR machinery is not ready for action anywhere. Only a cell nucleus with an intact envelope structure provides the adequate concentration of proteins for interacting with damaged DNA and triggering an efficient DDR. In the case of micronuclear DNA lesions, the chromatin encapsulated in micronuclei does not benefit from the intricate and efficient web of DDR players of the cell, and chromosome instability would be favored under these circumstances if micronuclei were reincorporated into daughter nuclei. In this sense, it has recently been observed that after nuclear breakdown, some whole-chromosome containing micronuclei might join the other mitotic chromosomes and be distributed to daughter nuclei [32,58]. By photoactivation of the micronuclear chromatin and its subsequent tracking, these authors observed that almost 1/3 of micronuclei reincorporate into daughter nuclei. The remaining micronuclei persisted in cells well into the second generation. Therefore, if lesions are produced in the micronuclear DNA previous to its reincorporation, as DDR is impeded in the micronuclear environment, the damaged micronuclear chromatin could be a source for chromosome instability under certain circumstances (Figure 3). If micronuclei with damaged DNA can finally be reincorporated in the main pool of chromosomes, the presence of unrepaired lesions could certainly increase genomic instability, in terms of gene loss and mutation rate, in the recipient cell. Micronuclei, which have mainly been considered as indicators of ongoing chromosome instability, now emerge as a source of instability at the same time. Altogether, this reveals a new dimension in the significance of micronucleation in the carcinogenesis process.


Is DNA damage response ready for action anywhere?

Terradas M, Martín M, Hernández L, Tusell L, Genescà A - Int J Mol Sci (2012)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472763&req=5

f3-ijms-13-11569: 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.
Mentions: The collected data suggest that the DDR machinery is not ready for action anywhere. Only a cell nucleus with an intact envelope structure provides the adequate concentration of proteins for interacting with damaged DNA and triggering an efficient DDR. In the case of micronuclear DNA lesions, the chromatin encapsulated in micronuclei does not benefit from the intricate and efficient web of DDR players of the cell, and chromosome instability would be favored under these circumstances if micronuclei were reincorporated into daughter nuclei. In this sense, it has recently been observed that after nuclear breakdown, some whole-chromosome containing micronuclei might join the other mitotic chromosomes and be distributed to daughter nuclei [32,58]. By photoactivation of the micronuclear chromatin and its subsequent tracking, these authors observed that almost 1/3 of micronuclei reincorporate into daughter nuclei. The remaining micronuclei persisted in cells well into the second generation. Therefore, if lesions are produced in the micronuclear DNA previous to its reincorporation, as DDR is impeded in the micronuclear environment, the damaged micronuclear chromatin could be a source for chromosome instability under certain circumstances (Figure 3). If micronuclei with damaged DNA can finally be reincorporated in the main pool of chromosomes, the presence of unrepaired lesions could certainly increase genomic instability, in terms of gene loss and mutation rate, in the recipient cell. Micronuclei, which have mainly been considered as indicators of ongoing chromosome instability, now emerge as a source of instability at the same time. Altogether, this reveals a new dimension in the significance of micronucleation in the carcinogenesis process.

Bottom Line: This response has to be rapid and accurate in order to keep genome integrity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain; E-Mails: marta.martin@uab.cat (M.M.); laia.hernandez@uab.cat (L.H.); laura.tusell@uab.cat (L.T.); anna.genesca@uab.cat (A.G.).

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.

Show MeSH
Related in: MedlinePlus