Limits...
The heterochromatic barrier to DNA double strand break repair: how to get the entry visa.

Goodarzi AA, Jeggo PA - Int J Mol Sci (2012)

Bottom Line: Over recent decades, a deep understanding of pathways that repair DNA double strand breaks (DSB) has been gained from biochemical, structural, biophysical and cellular studies.Chromatin is broadly divided into open, transcriptionally active, euchromatin (EC) and highly compacted, transcriptionally inert, heterochromatin (HC), although these represent extremes of a spectrum.Moreover, DSBs within HC (HC-DSBs) are rapidly relocalized to the EC-HC interface.

View Article: PubMed Central - PubMed

Affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.

ABSTRACT
Over recent decades, a deep understanding of pathways that repair DNA double strand breaks (DSB) has been gained from biochemical, structural, biophysical and cellular studies. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent the two major DSB repair pathways, and both processes are now well understood. Recent work has demonstrated that the chromatin environment at a DSB significantly impacts upon DSB repair and that, moreover, dramatic modifications arise in the chromatin surrounding a DSB. Chromatin is broadly divided into open, transcriptionally active, euchromatin (EC) and highly compacted, transcriptionally inert, heterochromatin (HC), although these represent extremes of a spectrum. The HC superstructure restricts both DSB repair and damage response signaling. Moreover, DSBs within HC (HC-DSBs) are rapidly relocalized to the EC-HC interface. The damage response protein kinase, ataxia telangiectasia mutated (ATM), is required for HC-DSB repair but is dispensable for the relocalization of HC-DSBs. It has been proposed that ATM signaling enhances HC relaxation in the DSB vicinity and that this is a prerequisite for HC-DSB repair. Hence, ATM is essential for repair of HC-DSBs. Here, we discuss how HC impacts upon the response to DSBs and how ATM overcomes the barrier that HC poses to repair.

Show MeSH

Related in: MedlinePlus

Differential irradiation induced foci (IRIF) formation between Euchromatin and Heterochromatin. (1) DNA double strand breaks (DSBs) form within either heterochromatin (red) or euchromatin (blue); (2) γH2AX occurs on chromatin at the DSB site (green) enabling the formation of the larger IRIF (yellow star) comprised of proteins such as Mre11, Rad50, NBS1, MDC1, RNF8, RNF168 and 53BP1. In heterochromatin, however, IRIF fail to form to a similar extent (or at all) at the same time point. Rather, the heterochromatic DSB relocates from the heterochromatic core to the peripheral zone bordering on euchromatin; (3) Once relocated to the heterochromatin:euchromatin border, the heterochromatic DSB elicits IRIF formation which expands into the surrounding euchromatic space.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3472778&req=5

f1-ijms-13-11844: Differential irradiation induced foci (IRIF) formation between Euchromatin and Heterochromatin. (1) DNA double strand breaks (DSBs) form within either heterochromatin (red) or euchromatin (blue); (2) γH2AX occurs on chromatin at the DSB site (green) enabling the formation of the larger IRIF (yellow star) comprised of proteins such as Mre11, Rad50, NBS1, MDC1, RNF8, RNF168 and 53BP1. In heterochromatin, however, IRIF fail to form to a similar extent (or at all) at the same time point. Rather, the heterochromatic DSB relocates from the heterochromatic core to the peripheral zone bordering on euchromatin; (3) Once relocated to the heterochromatin:euchromatin border, the heterochromatic DSB elicits IRIF formation which expands into the surrounding euchromatic space.

Mentions: Whilst some observations described above may be attributed to DSB movement within HC, there is distinct evidence that HC is refractory to IRIF expansion; for example, in the studies of Kim et al., γH2AX modifications originating from an HO-induced DSB penetrate avidly into EC but not HC [24]. Further, a distinct approach has shown enhanced expansion of γH2AX foci at DSBs within HC relaxed by inhibition, depletion or mutation of defined HC proteins [26,33]. For example, greater γH2AX expansion is observed following addition of HDAC chemical inhibitors [26,34]. Such a consequence may not be unique to HC proteins, however, since haploinsufficiency of histone H1 has similarly been reported to confer an increase in the magnitude of DDR signaling, observed as enhanced phosphorylation of ATM substrates [35]. However, of more relevance in the present context, is the finding that depletion of the KRAB-associated protein 1 (KAP-1) co-repressor, a critical HC building factor, similarly led to enlarged IRIF. Moreover, a number of human disorders with disordered HC have been described, including immunodeficiency, centromeric region, facial anomalies syndrome type A (ICFa, caused by mutations in the DNA methyltransferase, DNMT3B), Hutchinson-Guildford Progeria syndrome (HGPS, caused by mutations in the nuclear envelope protein lamin A) and Rett syndrome (caused by mutations in a methyl-(CpG) DNA binding protein, MeCP2). Interestingly, cells derived from such patients also show larger γH2AX foci compared to those observed in control cell lines [33]. Moreover, the larger foci are predominantly due to enhanced encroachment of γH2AX foci into the dense DAPI-staining regions. Collectively, a broad range of studies have provided substantial evidence that HC is a barrier to the expansion of γH2AX spreading, although as a separate and potentially confusing issue, DSBs also relocate to the interface between HC and EC regions (depicted in Figure 1).


The heterochromatic barrier to DNA double strand break repair: how to get the entry visa.

Goodarzi AA, Jeggo PA - Int J Mol Sci (2012)

Differential irradiation induced foci (IRIF) formation between Euchromatin and Heterochromatin. (1) DNA double strand breaks (DSBs) form within either heterochromatin (red) or euchromatin (blue); (2) γH2AX occurs on chromatin at the DSB site (green) enabling the formation of the larger IRIF (yellow star) comprised of proteins such as Mre11, Rad50, NBS1, MDC1, RNF8, RNF168 and 53BP1. In heterochromatin, however, IRIF fail to form to a similar extent (or at all) at the same time point. Rather, the heterochromatic DSB relocates from the heterochromatic core to the peripheral zone bordering on euchromatin; (3) Once relocated to the heterochromatin:euchromatin border, the heterochromatic DSB elicits IRIF formation which expands into the surrounding euchromatic space.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472778&req=5

f1-ijms-13-11844: Differential irradiation induced foci (IRIF) formation between Euchromatin and Heterochromatin. (1) DNA double strand breaks (DSBs) form within either heterochromatin (red) or euchromatin (blue); (2) γH2AX occurs on chromatin at the DSB site (green) enabling the formation of the larger IRIF (yellow star) comprised of proteins such as Mre11, Rad50, NBS1, MDC1, RNF8, RNF168 and 53BP1. In heterochromatin, however, IRIF fail to form to a similar extent (or at all) at the same time point. Rather, the heterochromatic DSB relocates from the heterochromatic core to the peripheral zone bordering on euchromatin; (3) Once relocated to the heterochromatin:euchromatin border, the heterochromatic DSB elicits IRIF formation which expands into the surrounding euchromatic space.
Mentions: Whilst some observations described above may be attributed to DSB movement within HC, there is distinct evidence that HC is refractory to IRIF expansion; for example, in the studies of Kim et al., γH2AX modifications originating from an HO-induced DSB penetrate avidly into EC but not HC [24]. Further, a distinct approach has shown enhanced expansion of γH2AX foci at DSBs within HC relaxed by inhibition, depletion or mutation of defined HC proteins [26,33]. For example, greater γH2AX expansion is observed following addition of HDAC chemical inhibitors [26,34]. Such a consequence may not be unique to HC proteins, however, since haploinsufficiency of histone H1 has similarly been reported to confer an increase in the magnitude of DDR signaling, observed as enhanced phosphorylation of ATM substrates [35]. However, of more relevance in the present context, is the finding that depletion of the KRAB-associated protein 1 (KAP-1) co-repressor, a critical HC building factor, similarly led to enlarged IRIF. Moreover, a number of human disorders with disordered HC have been described, including immunodeficiency, centromeric region, facial anomalies syndrome type A (ICFa, caused by mutations in the DNA methyltransferase, DNMT3B), Hutchinson-Guildford Progeria syndrome (HGPS, caused by mutations in the nuclear envelope protein lamin A) and Rett syndrome (caused by mutations in a methyl-(CpG) DNA binding protein, MeCP2). Interestingly, cells derived from such patients also show larger γH2AX foci compared to those observed in control cell lines [33]. Moreover, the larger foci are predominantly due to enhanced encroachment of γH2AX foci into the dense DAPI-staining regions. Collectively, a broad range of studies have provided substantial evidence that HC is a barrier to the expansion of γH2AX spreading, although as a separate and potentially confusing issue, DSBs also relocate to the interface between HC and EC regions (depicted in Figure 1).

Bottom Line: Over recent decades, a deep understanding of pathways that repair DNA double strand breaks (DSB) has been gained from biochemical, structural, biophysical and cellular studies.Chromatin is broadly divided into open, transcriptionally active, euchromatin (EC) and highly compacted, transcriptionally inert, heterochromatin (HC), although these represent extremes of a spectrum.Moreover, DSBs within HC (HC-DSBs) are rapidly relocalized to the EC-HC interface.

View Article: PubMed Central - PubMed

Affiliation: Southern Alberta Cancer Research Institute, Departments of Biochemistry & Molecular Biology and Oncology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.

ABSTRACT
Over recent decades, a deep understanding of pathways that repair DNA double strand breaks (DSB) has been gained from biochemical, structural, biophysical and cellular studies. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent the two major DSB repair pathways, and both processes are now well understood. Recent work has demonstrated that the chromatin environment at a DSB significantly impacts upon DSB repair and that, moreover, dramatic modifications arise in the chromatin surrounding a DSB. Chromatin is broadly divided into open, transcriptionally active, euchromatin (EC) and highly compacted, transcriptionally inert, heterochromatin (HC), although these represent extremes of a spectrum. The HC superstructure restricts both DSB repair and damage response signaling. Moreover, DSBs within HC (HC-DSBs) are rapidly relocalized to the EC-HC interface. The damage response protein kinase, ataxia telangiectasia mutated (ATM), is required for HC-DSB repair but is dispensable for the relocalization of HC-DSBs. It has been proposed that ATM signaling enhances HC relaxation in the DSB vicinity and that this is a prerequisite for HC-DSB repair. Hence, ATM is essential for repair of HC-DSBs. Here, we discuss how HC impacts upon the response to DSBs and how ATM overcomes the barrier that HC poses to repair.

Show MeSH
Related in: MedlinePlus