Chromatin dynamics during DSB repair

Falk, Martin; Lukášová, Emı́lie; Gabrielová, Barbora; Ondřej, Vladan; Kozubek, Stanislav

doi:10.1016/j.bbamcr.2007.07.002

Cited by 120 publications

(112 citation statements)

References 40 publications

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“…Considering that the volume of a typical mammalian cell nucleus is about 250 mm 3 , a single treatment can, thus, result in multiple accidental DSB interactions leading to chromosome rearrangements. Fusions between IRIF have been reported in cells exposed to alpha particles (Aten et al, 2004) and X-rays (Falk et al, 2007). Thus, the 2.2-and 3.2-fold increases in nuclear area roamed by DSBs induced by ionizing radiation and etoposide, when compared with that of undamaged chromatin, would be expected to increase the probability of DSB interactions.…”

Section: Discussionmentioning

confidence: 99%

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Chromatin mobility is increased at sites of DNA double-strand breaks

Krawczyk¹,

Borovski²,

Stap³

et al. 2012

Journal of Cell Science

134

146

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SummaryDNA double-strand breaks (DSBs) can efficiently kill cancer cells, but they can also produce unwanted chromosome rearrangements when DNA ends from different DSBs are erroneously joined. Movement of DSB-containing chromatin domains might facilitate these DSB interactions and promote the formation of chromosome rearrangements. Therefore, we analyzed the mobility of chromatin domains containing DSBs, marked by the fluorescently tagged DSB marker 53BP1, in living mammalian cells and compared it with the mobility of undamaged chromatin on a time-scale relevant for DSB repair. We found that chromatin domains containing DSBs are substantially more mobile than intact chromatin, and are capable of roaming a more than twofold larger area of the cell nucleus. Moreover, this increased DSB mobility, but not the mobility of undamaged chromatin, can be reduced by agents that affect higher-order chromatin organization.

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Section: Discussionmentioning

confidence: 99%

“…Falk et al, 2007;Ziv et al, 2006). It is tempting to speculate that low-density chromatin would be more mobile than condensed chromatin.…”

Section: Irif Mobility Depends On Chromatin Organization and Varies Wmentioning

confidence: 99%

Chromatin mobility is increased at sites of DNA double-strand breaks

Krawczyk¹,

Borovski²,

Stap³

et al. 2012

Journal of Cell Science

134

146

View full text Add to dashboard Cite

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“…Third is that the demethylase activity of KDM4D facilitates the accessibility of ATM kinase to its substrates, which can be achieved by relaxing the chromatin structure through local demethylation of H3K9me2/me3 surrounding the DNA damage sites. Indeed, it was shown that the levels of H3K9me2/3 in γH2AX-positive regions decrease after damage (29,45).…”

Section: Kdm4d Affects the Ir-induced Foci Formation Of Rad51 And 53bp1mentioning

confidence: 99%

PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair

Khoury-Haddad

Guttmann‐Raviv

Ipenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

130

162

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Members of the lysine (K)-specific demethylase 4 (KDM4) A-D family of histone demethylases are dysregulated in several types of cancer. Here, we reveal a previously unrecognized role of KDM4D in the DNA damage response (DDR). We show that the C-terminal region of KDM4D mediates its rapid recruitment to DNA damage sites. Interestingly, this recruitment is independent of the DDR sensor ataxia telangiectasia mutated (ATM), but dependent on poly (ADP-ribose) polymerase 1 (PARP1), which ADP ribosylates KDM4D after damage. We demonstrate that KDM4D is required for efficient phosphorylation of a subset of ATM substrates. We note that KDM4D depletion impairs the DNA damage-induced association of ATM with chromatin, explaining its effect on ATM substrate phosphorylation. Consistent with an upstream role in DDR, KDM4D knockdown disrupts the damage-induced recombinase Rad51 and tumor protein P53 binding protein foci formation. Consequently, the integrity of homology-directed repair and nonhomologous end joining of DNA breaks is impaired in KDM4D-deficient cells. Altogether, our findings implicate KDM4D in DDR, furthering the links between the cancer-relevant networks of epigenetic regulation and genome stability.histone demethylation | chromosome instability | PARylation

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“…56 Moreover, decrease in the levels of H3K9me2/3 at gH2AX-positive regions was reported at 20 minutes after IR in mammalian cells. 87 Similarly, Young and colleagues observed local reduction in H3K9me3 levels at sites of damage in cells expressing low to moderate levels of EGFP-KDM4B fusion. 57 In contrast, a recent study reported local increase in H3K9me2/3 at DSB sites, 88 suggesting that H3K9 methylation levels at DNA damage sites are highly dynamics and might be also influenced by the chromatin context at the DNA breakage sites.…”

Section: Dna Damage-induced Substrates Of Kdmsmentioning

confidence: 99%

The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites

et al. 2015

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KDM4D is a lysine demethylase that removes tri-and di-methylated residues from H3K9 and is involved in transcriptional regulation and carcinogenesis. We recently showed that KDM4D is recruited to DNA damage sites in a PARP1-dependent manner and facilitates double-strand break repair in human cells. Moreover, we demonstrated that KDM4D is an RNA binding protein and mapped its RNA-binding motifs. Interestingly, KDM4D-RNA interaction is essential for its localization on chromatin and subsequently for efficient demethylation of its histone substrate H3K9me3. Here, we provide new data that shed mechanistic insights into KDM4D accumulation at DNA damage sites. We show for the first time that KDM4D binds poly(ADP-ribose) (PAR) in vitro via its C-terminal region. In addition, we demonstrate that KDM4D-RNA interaction is required for KDM4D accumulation at DNA breakage sites. Finally, we discuss the recruitment mode and the biological functions of additional lysine demethylases including KDM4B, KDM5B, JMJD1C, and LSD1 in DNA damage response.

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Chromatin dynamics during DSB repair

Cited by 120 publications

References 40 publications

Chromatin mobility is increased at sites of DNA double-strand breaks

Chromatin mobility is increased at sites of DNA double-strand breaks

PARP1-dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair

The emerging role of lysine demethylases in DNA damage response: dissecting the recruitment mode of KDM4D/JMJD2D to DNA damage sites

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