MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks

Stucki, Manuel; Clapperton, Julie A.; Mohammad, Duaa H.; Yaffe, Michael B.; Smerdon, Stephen J.; Jackson, Stephen

doi:10.1016/j.cell.2008.04.021

Cited by 146 publications

(215 citation statements)

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“…MDC1 is an adaptor protein that directly binds to γ‐H2AX to facilitate H2AX‐phosphorylation by ATM and promote accumulation of DNA damage response proteins to DNA double‐strand breaks . In HeLa cells, approximately 35% of prometaphase kinetochores exhibit MDC1 staining and inhibition of ATM by a small‐molecule inhibitor reduces MDC1 localization to kinetochores compared with controls .…”

Section: Dna Damage Proteins In Chromosome Segregation and Spindle Chmentioning

confidence: 99%

DNA damage response proteins regulating mitotic cell division: double agents preserving genome stability

Petsalaki

Zachos

2020

The FEBS Journal

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The DNA damage response recognizes DNA lesions and coordinates a cell cycle arrest with the repair of the damaged DNA, or removal of the affected cells to prevent the passage of genetic alterations to the next generation. The mitotic cell division, on the other hand, is a series of processes that aims to accurately segregate the genomic material from the maternal to the two daughter cells. Despite their great importance in safeguarding genomic integrity, the DNA damage response and the mitotic cell division were long viewed as unrelated processes, mainly because animal cells that are irradiated during mitosis continue cell division without repairing the broken chromosomes. However, recent studies have demonstrated that DNA damage proteins play an important role in mitotic cell division. This is performed through regulation of the onset of mitosis, mitotic spindle formation, correction of misattached kinetochore–microtubules, spindle checkpoint signaling, or completion of cytokinesis (abscission), in the absence of DNA damage. In this review, we summarize the roles of DNA damage proteins in unperturbed mitosis, analyze the molecular mechanisms involved, and discuss the potential implications of these findings in cancer therapy.

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Section: Dna Damage Proteins In Chromosome Segregation and Spindle Chmentioning

confidence: 99%

DNA damage response proteins regulating mitotic cell division: double agents preserving genome stability

Petsalaki

Zachos

2020

The FEBS Journal

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“…To determine whether ␥-H2AX formation might promote ATM activation, in a positive-feedback loop (Stucki et al, 2005;Lou et al, 2006), we compared the kinetics of ATM activation in MEFs lacking H2AX (H2AX-KO) and their wild-type counterparts (H2AX-WT; Celeste et al, 2002). Figure 8C shows reduced ATM activation in the H2AX-KO cells, indicating that H2AX is necessary for the full activation of ATM after Et743 treatment.…”

Section: H2ax Is Necessary For the Full Activation Of Atmmentioning

confidence: 99%

Transcription-coupled DNA Double-Strand Breaks Are Mediated via the Nucleotide Excision Repair and the Mre11-Rad50-Nbs1 Complex

Guirouilh‐Barbat

Redon

Pommier

2008

MBoC

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The cellular activity of Yondelis (trabectedin, Ecteinascidin 743, Et743) is known to depend on transcription-coupled nucleotide excision repair (TCR). However, the subsequent cellular effects of Et743 are not fully understood. Here we show that Et743 induces both transcription- and replication-coupled DNA double-strand breaks (DSBs) that are detectible by neutral COMET assay and as gamma-H2AX foci that colocalize with 53BP1, Mre11, Ser(1981)-pATM, and Thr(68)-pChk2. The transcription coupled-DSBs (TC-DSBs) induced by Et743 depended both on TCR and Mre11-Rad50-Nbs1 (MRN) and were associated with DNA-PK-dependent gamma-H2AX foci. In contrast to DNA-PK, ATM phosphorylated H2AX both in NER-proficient and -deficient cells, but its full activation was dependent on H2AX as well as DNA-PK, suggesting a positive feedback loop: DNA-PK-gamma-H2AX-ATM. Knocking-out H2AX or inactivating DNA-PK reduced Et743's antiproliferative activity, whereas ATM and MRN tended to act as survival factors. Our results highlight the interplays between ATM and DNA-PK and their impacts on H2AX phosphorylation and cell survival. They also suggest that gamma-H2AX may serve as a biomarker in patients treated with Et743 and that molecular profiling of tumors for TCR, MRN, ATM, and DNA-PK might be useful to anticipate tumor response to Et743 treatment.

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“…Following DNA damage, the Mre11/Rad50/Nbs1 (MRN) complex recognizes the break and contributes to the activation of ATM leading to the phosphorylation of H2AX across kilobases of DNA surrounding the damaged site (Shroff et al , 2004). A cascade of protein relocalization is then triggered by the binding of the mediator protein MDC1 to phosphorylated H2AX (γH2AX) through its BRCT domain (Stucki et al , 2005). MDC1 then amplifies the DNA damage signalling response by coordinating the assembly of checkpoint and repair proteins (Goldberg et al , 2003; Lou et al , 2003, 2006; Stewart et al , 2003; Bekker‐Jensen et al , 2005).…”

Section: Introductionmentioning

confidence: 99%

RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites

et al. 2012

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In response to DNA damage, cells initiate complex signalling cascades leading to growth arrest and DNA repair. The recruitment of 53BP1 to damaged sites requires the activation of the ubiquitination cascade controlled by the E3 ubiquitin ligases RNF8 and RNF168, and methylation of histone H4 on lysine 20. However, molecular events that regulate the accessibility of methylated histones, to allow the recruitment of 53BP1 to DNA breaks, are unclear. Here, we show that like 53BP1, the JMJD2A (also known as KDM4A) tandem tudor domain binds dimethylated histone H4K20; however, JMJD2A is degraded by the proteasome following the DNA damage in an RNF8‐dependent manner. We demonstrate that JMJD2A is ubiquitinated by RNF8 and RNF168. Moreover, ectopic expression of JMJD2A abrogates 53BP1 recruitment to DNA damage sites, indicating a role in antagonizing 53BP1 for methylated histone marks. The combined knockdown of JMJD2A and JMJD2B significantly rescued the ability of RNF8‐ and RNF168‐deficient cells to form 53BP1 foci. We propose that the RNF8‐dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites.

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MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks

Cited by 146 publications

References 0 publications

DNA damage response proteins regulating mitotic cell division: double agents preserving genome stability

DNA damage response proteins regulating mitotic cell division: double agents preserving genome stability

Transcription-coupled DNA Double-Strand Breaks Are Mediated via the Nucleotide Excision Repair and the Mre11-Rad50-Nbs1 Complex

RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites

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