53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer

DiTullio, Richard A.; Mochan, Tamara A.; Venere, Monica; Bártková, Jiřina; Sehested, Maxwell; Bártek, Jiří; Halazonetis, Thanos D.

doi:10.1038/ncb892

Cited by 388 publications

(363 citation statements)

References 24 publications

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“…The phosphorylation of Chk1 kinase, a mediator of DNA damage signaling, was more pronounced after knockdown of FATS expression in mouse embryonic fibroblast (MEF) cells after IR treatment (Figure 3b). To further verify this observation, we examined the effect of FATS knockdown on IR-induced nuclear foci of 53BP1, a mediator of DNA damage signaling (DiTullio et al, 2002). The nuclear staining of 53BP1 in unstressed cells was diffused, and a few nuclear foci of 53BP1 were observed 3 h after IR treatment in MEF cells.…”

Section: Resultsmentioning

confidence: 94%

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Zhang

Mao

et al. 2010

Oncogene

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There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genomewide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.

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Section: Resultsmentioning

confidence: 94%

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Zhang

Mao

et al. 2010

Oncogene

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“…The former variability likely reflects the diverse genetic backgrounds in our models, particularly the status of the p53 and RB tumor suppressors whose defects (in MDA-MB-468 and HS913T cells) correlated with rather poor responses compared with p53/RBproficient U2OS and A549 cells. RB and p53 are critical for proper execution of senescence (Collado et al, 2007; and their defects are often accompanied by enhanced constitutive DNA damage (DiTullio et al, 2002), also because such tumors breached the anticancer barrier of DNA damage checkpoints and senescence Halazonetis et al, 2008). The fact that HeLa cells responded relatively well to genotoxic drugs may reflect BrdU/ DMA-induced degradation of the papilloma virus oncoproteins E6 and E7 (Suzuki et al, 2001), thereby liberating the endogenous p53 and RB functions, and hence promoting the senescence response.…”

Section: Discussionmentioning

confidence: 99%

Cytokine expression and signaling in drug-induced cellular senescence

et al. 2009

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Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2 0 -deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon c (IFNc), IFNb and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/ chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNb-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.

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“…Insights into both of these fundamental issues have recently been obtained and helped to formulate the concept of DDR activation in response to tumorigenic insults and a candidate biological barrier that delays or prevents cancer progression in vivo. Arguably, the key initial observations that inspired the DDR barrier hypothesis were those of constitutively activated DNA damage signalling in subsets of human cancer cell lines, especially those defective in p53 function, and a broadly analogous phenomenon of chronically active DNA damage checkpoints, as exemplified by the presence of Thr68-phosphorylated, activated form of the checkpoint kinase Chk2 in clinical specimens of large subsets of human breast and lung carcinomas (DiTullio et al, 2002). Given that the biopsy specimens from such tumours were surgically removed before the patients were exposed to any adjuvant treatment, such constitutive DNA damage checkpoint signalling was not attributable to radiotherapy or chemotherapy.…”

Section: Dna Damage Response As An Anticancer Barrier: Initial Observmentioning

confidence: 99%

DNA damage signalling guards against activated oncogenes and tumour progression

2007

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DNA damage response (DDR), the guardian of genomic integrity, emerges as an oncogene-inducible biological barrier against progression of cancer beyond its early stages. Recent evidence from both cell culture and animal models as well as analyses of clinical specimens show that activation of numerous oncogenes and loss of some tumour suppressors result in DNA replication stress and DNA damage that alarm the cellular DDR machinery, a multifaceted response orchestrated by the ATR-Chk1 and ATM-Chk2 kinase signalling pathways. Such activation of the DDR network leads to cellular senescence or death of oncogene-transformed cells, resulting in delay or prevention of tumorigenesis. At the same time, the ongoing chronic DDR activation creates selective pressure that eventually favours outgrowth of malignant clones with genetic or epigenetic defects in the genome maintenance machinery, such as aberrations in the ATMChk2-p53 cascade and other DDR components. Furthermore, the executive DDR machinery is shared by at least two anticancer barriers, as both the oncogene-induced DNA replication stress and telomere shortening impact the cell fate decisions through convergence on DNA damage signalling. In this study, we highlight recent advances in this rapidly evolving area of cancer research, with particular emphasis on mechanistic insights, emerging issues of special conceptual significance and discussion of major remaining challenges and implications of the concept of DDR as a tumorigenesis barrier for experimental and clinical oncology.

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53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer

Cited by 388 publications

References 24 publications

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis

Cytokine expression and signaling in drug-induced cellular senescence

DNA damage signalling guards against activated oncogenes and tumour progression

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