MDC1 Maintains Genomic Stability by Participating in the Amplification of ATM-Dependent DNA Damage Signals

Lou, Zhenkun; Minter-Dykhouse, Katherine; Franco, Sonia; Gostissa, Monica; Rivera, Melissa A.; Celeste, Arkady; Manis, John P.; Deursen, Jan van; Nussenzweig, André; Paull, Tanya T.; Alt, Frederick W.; Chen, Junjie

doi:10.1016/j.molcel.2005.11.025

Cited by 560 publications

(627 citation statements)

References 44 publications

Supporting

Mentioning

578

Contrasting

Unclassified

Order By: Relevance

“…It is difficult to test the former, since normal numbers of gH2AX foci are observed even in the absence of ATM (McManus and Hendzel, 2005). In addition, while further activation involves MRN, it is also evident that MDC1 plays an important role in amplifying ATM-dependent DNA-damage signalling (Bekker-Jensen et al, 2006;Lou et al, 2006). This may be a later event with MDC1, providing a platform to stabilize the complex and sustain ATM signalling.…”

Section: Perspectivementioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

View full text Add to dashboard Cite

The recognition and repair of DNA double-strand breaks (DSBs) is a complex process that draws upon a multitude of proteins. This is not surprising since this is a lethal lesion if left unrepaired and also contributes to genome instability and the consequential risk of cancer and other pathologies. Some of the key proteins that recognize these breaks in DNA are mutated in distinct genetic disorders that predispose to agent sensitivity, genome instability, cancer predisposition and/or neurodegeneration. These include members of the Mre11 complex (Mre11/Rad50/ Nbs1) and ataxia-telangiectasia (A-T) mutated (ATM), mutated in the human genetic disorder A-T. The mre11 (MRN) complex appears to be the major sensor of the breaks and subsequently recruits ATM where it is activated to phosphorylate in turn members of that complex and a variety of other proteins involved in cellcycle control and DNA repair. The MRN complex is also upstream of ATM and ATR (A-T-mutated and rad3-related) protein in responding to agents that block DNA replication. To date, more than 30 ATM-dependent substrates have been identified in multiple pathways that maintain genome stability and reduce the risk of disease. We focus here on the relationship between ATM and the MRN complex in recognizing and responding to DNA DSBs.

show abstract

Section: Perspectivementioning

confidence: 99%

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

2007

View full text Add to dashboard Cite

show abstract

“…While H2AX is not strictly required for development in the mouse, its loss predisposes to genomic instability (Celeste et al, 2002(Celeste et al, , 2003. H2AX phosphorylation results in recruitment of mediator of DNA damage checkpoint protein 1 to the DNA break (Goldberg et al, 2003;Lou et al, 2003;Stewart et al, 2003), via binding to the g-H2AX C terminus, and this interaction is required for signal amplification and effective modulation of downstream ATM signaling (Bekker-Jensen et al, 2005;Stucki et al, 2005;Lou et al, 2006;Stucki and Jackson, 2006).…”

Section: Defective Dna Dsb Responses and A-t-related Syndromesmentioning

confidence: 99%

DNA double-strand break repair and development

Phillips

McKinnon

2007

Oncogene

View full text Add to dashboard Cite

Normal development of an organism requires the ability to respond to DNA damage. A particularly deleterious lesion is a DNA double-strand break (DSB). The cellular response to DNA DSBs occurs via an integrated sensing and signaling network that maintains genomic stability. The outcomes of defective DNA DSB repair are related to the developmental stage of an organism, and often show striking tissue specificity. Many human diseases are associated with deficiencies in DNA DSB repair and can be characterized by neuropathology, immune deficiency, growth retardation or predisposition to cancer. This review will focus on the requirements of the DNA DSB response that function to maintain homeostasis during mammalian development.

show abstract

“…As the ATM protein kinase is the major H2AX kinase after induction of DSBs, the main function of ATM could be creation of a chromatin environment that facilitates MRN accumulation in nuclear foci. This notion is supported by the observation, that cells deficient in all these repair factors have similar repair defects, most notably increased levels of residual DSBs after ionizing radiation and chromosomal instability (Ward et al, 2003;Franco et al, 2006;Lou et al, 2006;Lavin and Kozlov, 2007).…”

Section: Other Accessory Factors For Nhejmentioning

confidence: 77%

Non-homologous end-joining, a sticky affair

2007

View full text Add to dashboard Cite

Rejoining of broken chromosomes is crucial for cell survival and prevention of malignant transformation. Most mammalian cells rely primarily on the non-homologous end-joining pathway of DNA double-strand break (DSB) repair to accomplish this task. This review focuses both on the core non-homologous end-joining machinery, which consists of DNA-dependent protein kinase and the ligase IV/XRCC4 complex, and on accessory factors that facilitate rejoining of a subset of the DSBs. We discuss how the ATM protein kinase and the Mre11/Rad50/Nbs1 complex might function in DSB repair and what role ionizing radiation-induced foci may play in this process.

show abstract

MDC1 Maintains Genomic Stability by Participating in the Amplification of ATM-Dependent DNA Damage Signals

Cited by 560 publications

References 44 publications

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks

DNA double-strand break repair and development

Non-homologous end-joining, a sticky affair

Contact Info

Product

Resources

About