Mre11–Rad50–Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity

Jazayeri, Ali; Balestrini, Alessia; Garner, Elizabeth; Haber, James E.; Costanzo, Vincenzo

doi:10.1038/emboj.2008.128

Cited by 116 publications

(97 citation statements)

References 35 publications

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“…Recent studies have indicated that the MRN complex bound to DNA ends may directly activate ATM and/or initiate the nucleation of ATM at DSBs, which leads to its activation (Lee and Paull, 2005;Dupre et al, 2006). The recognition of DNA ends by the MRN complex may be a prerequisite for its DNA unwinding, tethering or nuclease activities implicated in ATM activation (Uziel et al, 2003;Costanzo et al, 2004;Jazayeri et al, 2008). Thus, it seems likely that the MRN complex and 53BP1 function both upstream and downstream of ATM after DNA damage.…”

Section: Pig3 Is Involved In the Cell-cycle Checkpoint Pathwaymentioning

confidence: 99%

The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage

et al. 2009

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The p53-inducible gene 3 (PIG3) is originally isolated as a p53 downstream target gene, but its function remains unknown. Here, we report a role of PIG3 in the activation of DNA damage checkpoints, after UV irradiation or radiomimetic drug neocarzinostatin (NCS). We show that depletion of endogenous PIG3 sensitizes cells to DNA damage agents, and impaired DNA repair. PIG3 depletion also allows for UV-and NCS-resistant DNA synthesis and permits cells to progress into mitosis, indicating that PIG3 knockdown can suppress intra-S phase and G2/M checkpoints. PIG3-depleted cells show reduced Chk1 and Chk2 phosphorylation after DNA damage, which may directly contribute to checkpoint bypass. PIG3 exhibited diffuse nuclear staining in the majority of untreated cells and forms discrete nuclear foci in response to DNA damage. PIG3 colocalizes with c-H2AX and 53BP1 to sites of DNA damage after DNA damage, and binds to a c-H2AX. Notably, PIG3 depletion decreases the efficient induction and maintenance of H2AX phosphorylation after DNA damage. Moreover, PIG3 contributes to the recruitment of 53BP1, Mre11, Rad50 and Nbs1 to the sites of DNA break lesions in response to DNA damage. Our combined results suggest that PIG3 is a critical component of the DNA damage response pathway and has a direct role in the transmission of the DNA damage signal from damaged DNA to the intra-S and G2/M checkpoint machinery in human cells.

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Section: Pig3 Is Involved In the Cell-cycle Checkpoint Pathwaymentioning

confidence: 99%

The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage

et al. 2009

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“…However, there is increasing evidence that by-products of DNA repair have the potential to impact cell signaling events (15)(16)(17)(18). Moreover, defects in the clearance of DNA oligonucleotides are associated with various autoimmune disorders (19 -21), and abnormal localization of DNA in the cytosol may be sensed by the innate immune system (22,23).…”

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confidence: 99%

DNA Repair Synthesis and Ligation Affect the Processing of Excised Oligonucleotides Generated by Human Nucleotide Excision Repair

Kemp

Gaddameedhi

Choi

et al. 2014

Journal of Biological Chemistry

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Background:The mechanism of excised oligonucleotide processing during nucleotide excision repair is unknown. Results: UV photoproduct-containing oligonucleotides associate with chromatin following the dual incisions. Inhibition of gap-filling activities results in an accumulation of RPA-bound small, excised, damaged DNA (sedDNA) fragments. Conclusion: Gap filling-mediated dissociation of sedDNAs from RPA influences nucleotide excision repair rate. Significance: sedDNA processing is important in the DNA damage response.

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“…7 DSB repair is believed to involve an Atm to Atr switch. 8,9 Atm is first recruited to DSBs and ssDNA is later generated by resection of the DNA ends, where Atr can be assembled and activated. Thus, there exists a complex functional interaction between these two PIKKs.…”

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confidence: 99%

A positive role for c-Abl in Atm and Atr activation in DNA damage response

et al. 2010

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DNA damage triggers Atm-and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. Cell Death and Differentiation (2011) 18, 5-15; doi:10.1038/cdd.2010; published online 27 August 2010 DNA damage can be caused by exogenous or endogenous factors such as ionizing radiation (IR), chemotherapeutic drugs, and stalled replication forks. 1 It is believed that various DNA lesions are eventually converted to double-stranded breaks (DSBs) and/or single-stranded DNA (ssDNA or SSBs), where sensors, mediators, transducers, and effectors assemble to form nuclear foci, which function as centers of signal propagation. At the core of the signaling network are PI-3 kinase-like kinases (PIKKs), including Atm, Atr and DNA-PKcs. 2 Atm is mainly activated by DSBs, whereas Atr responds to various DNA lesions. 3 Atm and Atr are recruited to the nuclear foci by the MRN (Mre11-Rad50-NBS) complex and ATRIP, respectively, 4,5 where they phosphorylate proteins such as p53, Chk1, Chk2, and H2AX, to activate cell cycle checkpoints and/or induce apoptosis. 6 Phosphorylation of Chk1 and Chk2 by Atr and Atm is facilitated by a group of nuclear foci proteins called mediators, for example, Brca1, TopBP1, and 53BP1. Furthermore, the nuclear foci also function as repair centers. 7 DSB repair is believed to involve an Atm to Atr switch. 8,9 Atm is first recruited to DSBs and ssDNA is later generated by resection of the DNA ends, where Atr can be assembled and activated. Thus, there exists a complex functional interaction between these two PIKKs. 10 Although several proteins have been reported to activate Atm or Atr, 11,12 the initial activation of Atm/Atr and the regulation of their activities in the process of DNA repair are poorly understood. 13,14 The c-Abl proto-oncogene encodes a non-receptor tyrosine kinase that is essential for perinatal survival in ...

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Mre11–Rad50–Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity

Cited by 116 publications

References 35 publications

The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage

The p53-inducible gene 3 (PIG3) contributes to early cellular response to DNA damage

DNA Repair Synthesis and Ligation Affect the Processing of Excised Oligonucleotides Generated by Human Nucleotide Excision Repair

A positive role for c-Abl in Atm and Atr activation in DNA damage response

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