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

Lavin, Martin F.

doi:10.1038/sj.onc.1210880

Cited by 258 publications

(206 citation statements)

References 76 publications

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“…MRN binds DNA breaks on chromatin independently of ATM but needs to recruit and activate ATM by phosphorylation before it can itself be phosphorylated and activated by ATM. This modification subsequently allows MRN to act as an adapter for downstream signaling to other ATM targets (reviewed in (42,43). Our data indicate that FANCM and FANCD2 affect each other's function during replication and the DNA damage response; however, because the molecular function of FANCD2 is currently unknown, further studies are necessary to investigate which function(s) of FANCD2 might be controlled by FANCM and vice versa during DNA damage signaling.…”

Section: Discussionmentioning

confidence: 93%

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Sobeck¹,

Stone

Landais

et al. 2009

Journal of Biological Chemistry

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In addition to monoubiquitination by the FA core complex, FANCD2 and FANCI are phosphorylated by the two major cell cycle checkpoint kinases, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related),y in response to DNA damage (2-6). ATM-dependent phosphorylation of FANCD2 occurs following ionizing irradiation and is required for activation of the ionizing irradiation-induced intra-S phase checkpoint (4). ATR-dependent phosphorylation of FANCD2 is triggered by various types of DNA damage, including replication stress, and is required for the interstrand cross-link-induced intra-S phase checkpoint response (2, 3). Moreover, phosphorylation by ATR is required for efficient FANCD2 monoubiquitination in response to DNA damage, suggesting that the FA pathway might participate in ATR-dependent coordination of the S phase of the cell cycle (3, 7).The recent identification of a highly conserved FA core complex member, FANCM (8, 9), indicates a direct role of FA pathway proteins in repair steps at sites of DNA damage. FANCM is a homolog of the archaebacterial Hef protein (helicase-associated endonuclease for fork-structured DNA) and contains two DNA processing domains: a DEAH box helicase domain and an XPF/ERCC4-like endonuclease domain. FANCM has ATP-dependent DNA translocase activity and can dissociate DNA triple helices in vitro (8). Moreover, FANCM binds Holliday junctions and DNA replication fork structures in vitro and promotes ATP-dependent branch point migration, suggesting that FANCM might be involved in DNA processing at stalled replication forks (10,11). In human cells, FANCM localizes to chromatin and is required for chromatin recruitment of other FA core complex proteins (8,12). FANCM is phosphorylated during both the M and S phases and in response to DNA-damaging agents (8,12,13). Interestingly, DNA damage-induced phosphorylation of FANCM is independent of the FA core complex (8), suggesting that FANCM is controlled by other, as yet unknown upstream components of the DNA damage response. Here, we used cell-free Xenopus egg extracts to investigate the role of FANCM during replication and in the DNA damage response. We show that Xenopus FANCM (xFANCM) binds chromatin in a replication-dependent manner and is phosphorylated during unperturbed replication as well as in response to various DNA damage structures. Both chromatin recruitment and phosphorylation of xFANCM are partially controlled by xFANCD2, suggesting feedback signaling from xFANCD2 to the upstream xFA core complex via regulation of xFANCM. In addition, chromatin recruitment during unperturbed replication and activation of xFANCM in response to DNA damage are controlled by the xATR and xATM cell cycle kinases.

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Section: Discussionmentioning

confidence: 93%

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Sobeck¹,

Stone

Landais

et al. 2009

Journal of Biological Chemistry

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“…ATM has been reported as a key sensor in response to DNA double strand breaks (Lavin, 2007;Lavin and Kozlov, 2007;Niida and Nakanishi, 2006) or DNA ends (Bolderson et al, 2004).…”

Section: Chapter 6 Discussionmentioning

confidence: 99%

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

2014

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“…The primary transducer of the DSB alarm is the nuclear serine-threonine kinase ATM (30). ATM then phosphorylates a plethora of effectors, which are key players in a variety of damage response pathways (30,31), including DNA repair, cell cycle checkpoints, and programmed cell death (32,33). Activated ATM phosphorylates, among others, the checkpoint protein kinase Chk2 on T68 (33,34).…”

Section: Resultsmentioning

confidence: 99%

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

Barash

Gross²,

Edrei³

et al. 2010

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

106

114

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and is considered to be the outcome of chronic liver inflammation. Currently, the main treatment for HCC is surgical resection. However, survival rates are suboptimal partially because of tumor recurrence in the remaining liver. Our aim was to understand the molecular mechanisms linking liver regeneration under chronic inflammation to hepatic tumorigenesis. Mdr2-KO mice, a model of inflammation-associated cancer, underwent partial hepatectomy (PHx), which led to enhanced hepatocarcinogenesis. Moreover, liver regeneration in these mice was severely attenuated. We demonstrate the activation of the DNA damage-response machinery and increased genomic instability during early liver inflammatory stages resulting in hepatocyte apoptosis, cell-cycle arrest, and senescence and suggest their involvement in tumor growth acceleration subsequent to PHx. We propose that under the regenerative proliferative stress induced by liver resection, the genomic unstable hepatocytes generated during chronic inflammation escape senescence and apoptosis and reenter the cell cycle, triggering the enhanced tumorigenesis. Thus, we clarify the immediate and long-term contributions of the DNA damage response to HCC development and recurrence. hepatocellular carcinoma | MRI | MDR2 -/-mice | genomic instability

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

Cited by 258 publications

References 76 publications

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks

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