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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

Model for nucleotide excision repair pathway including both subpathways: the global genomic repair (GGR) (left) and the transcription-coupled repair (TCR) (right).
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f1-ijms-13-11569: Model for nucleotide excision repair pathway including both subpathways: the global genomic repair (GGR) (left) and the transcription-coupled repair (TCR) (right).

Mentions: Although highly deleterious, DSBs are not the only lesions that DNA may suffer. Helix-distorting base lesions are indeed very frequent and are repaired by the nucleotide excision repair (NER) pathway, whose versatility accounts for the repair of a wide variety of lesions. In this sense, NER is in charge of repairing the DNA damage formed upon exposure to the UV radiation from sunlight and numerous bulky DNA adducts induced by mutagenic chemicals from the environment or by cytotoxic drugs used in chemotherapy [43]. The NER pathway consists of several steps, but the presence of distortion in the structure of the double helix or the chemical modification of the DNA is indispensable for its activation. NER can be subdivided into two different subpathways depending on the transcription state of the damaged genes: the global genomic repair (GGR) and the transcription-coupled repair (TCR) (Figure 1). Whereas in the first one the damage is detected by the collective action of the protein UV-DDB and the XPC containing complex, in the second one the lesions are recognized by the RNA polymerase II itself [44]. Once the lesions have been detected, both subpathways converge and the later steps of repair are conducted by a common set of protein factors [45,46]. At this point, the multi-functional complex TFIIH is recruited to the DNA damage site and unwinds the DNA to allow the other factors to reach the lesion. XPB and XPD are the helicase subunits of the TFIIH complex responsible for the 30 bp opening of the DNA, which is immediately stabilized by RPA through its binding to the undamaged strand [47,48]. Simultaneously, XPA binds to the 5′ end of the lesion, where it confirms the presence of damage by probing for abnormal backbone structure. When damage is absent, XPA aborts NER [45]. The stabilization of the damaged DNA allows the proper orientation of the two endonucleases that remove the damaged nucleotides: XPG and the complex XPF/ERCC1. While XPG cuts at the 3′ end of the lesion, XPF/ERCC1 cuts at the 5′ end, leaving a 25–30 nucleotides gap [49]. The gap is then filled by the DNA polymerases δ and ɛ, joined together by the sliding clamp PCNA, and sealed by the XRCC1-ligase III [50].


Is DNA damage response ready for action anywhere?

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

Model for nucleotide excision repair pathway including both subpathways: the global genomic repair (GGR) (left) and the transcription-coupled repair (TCR) (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-13-11569: Model for nucleotide excision repair pathway including both subpathways: the global genomic repair (GGR) (left) and the transcription-coupled repair (TCR) (right).
Mentions: Although highly deleterious, DSBs are not the only lesions that DNA may suffer. Helix-distorting base lesions are indeed very frequent and are repaired by the nucleotide excision repair (NER) pathway, whose versatility accounts for the repair of a wide variety of lesions. In this sense, NER is in charge of repairing the DNA damage formed upon exposure to the UV radiation from sunlight and numerous bulky DNA adducts induced by mutagenic chemicals from the environment or by cytotoxic drugs used in chemotherapy [43]. The NER pathway consists of several steps, but the presence of distortion in the structure of the double helix or the chemical modification of the DNA is indispensable for its activation. NER can be subdivided into two different subpathways depending on the transcription state of the damaged genes: the global genomic repair (GGR) and the transcription-coupled repair (TCR) (Figure 1). Whereas in the first one the damage is detected by the collective action of the protein UV-DDB and the XPC containing complex, in the second one the lesions are recognized by the RNA polymerase II itself [44]. Once the lesions have been detected, both subpathways converge and the later steps of repair are conducted by a common set of protein factors [45,46]. At this point, the multi-functional complex TFIIH is recruited to the DNA damage site and unwinds the DNA to allow the other factors to reach the lesion. XPB and XPD are the helicase subunits of the TFIIH complex responsible for the 30 bp opening of the DNA, which is immediately stabilized by RPA through its binding to the undamaged strand [47,48]. Simultaneously, XPA binds to the 5′ end of the lesion, where it confirms the presence of damage by probing for abnormal backbone structure. When damage is absent, XPA aborts NER [45]. The stabilization of the damaged DNA allows the proper orientation of the two endonucleases that remove the damaged nucleotides: XPG and the complex XPF/ERCC1. While XPG cuts at the 3′ end of the lesion, XPF/ERCC1 cuts at the 5′ end, leaving a 25–30 nucleotides gap [49]. The gap is then filled by the DNA polymerases δ and ɛ, joined together by the sliding clamp PCNA, and sealed by the XRCC1-ligase III [50].

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