Mec1/ATR regulates the generation of single-stranded DNA that attenuates Tel1/ATM signaling at DNA ends

Clerici, Michela; Trovesi, Camilla; Galbiati, Alessandro; Lucchini, Giovanna; Longhese, Maria Pia

doi:10.1002/embj.201386041

Cited by 58 publications

(76 citation statements)

References 66 publications

(123 reference statements)

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“…In contrast, the ATM inhibitor KU55933 has no detectable effect on the recruitment of RAD52 and RAD51C to transcriptionally active damage sites. This result suggests that loss of ATM-mediated transcription silencing (21,22) is not sufficient to alter the recruitment of HR factors (Fig. 3 C and D), suggesting that unlike canonical HR repair, a factor distinct from the DNA damage signaling pathway is responsible for the assembly of HR factors at active transcription sites.…”

Section: Rna Polymerase II Inhibition Affects the Recruitment Of Hr Fmentioning

confidence: 99%

DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination

Wei

Nakajima

Böhm

et al. 2015

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

131

138

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Damage repair mechanisms at transcriptionally active sites during the G0/G1 phase are largely unknown. To elucidate these mechanisms, we introduced genome site-specific oxidative DNA damage and determined the role of transcription in repair factor assembly. We find that KU and NBS1 are recruited to damage sites independent of transcription. However, assembly of RPA1, RAD51C, RAD51, and RAD52 at such sites is strictly governed by active transcription and requires both wild-type Cockayne syndrome protein B (CSB) function and the presence of RNA in the G0/G1 phase. We show that the ATPase activity of CSB is indispensable for loading and binding of the recombination factors. CSB counters radiation-induced DNA damage in both cells and zebrafish models. Taken together, our results have uncovered a novel, RNA-based recombination mechanism by which CSB protects genome stability from strand breaks at transcriptionally active sites and may provide insight into the clinical manifestations of Cockayne syndrome.NA double strand breaks (DSBs) are a most severe type of DNA damage caused by endogenous metabolic processes and exogenous exposure to radiation and chemicals. Unrepaired DSBs induce genomic instability, carcinogenesis, and premature aging. In mammalian cells, DSBs are repaired by either the nonhomologous end joining (NHEJ) or the homologous recombination (HR) pathway. Although it is a common understanding that HR primarily takes place in response to strand breaks in the S-G2 phases of the cell cycle where the undamaged sister chromatids are present as donor templates, recent studies have suggested that homologous pairing also occurs during the G0/G1 phase and is associated with transcription (1), although the mechanisms remain to be elucidated. At active transcription sites, RNA polymerase II (RNA POLII) can bypass base modifications such as 8-oxo guanine but not single strand breaks (SSBs) and DSBs (2-5), indicating that unrepaired strand breaks at transcriptionally active (TA) sites can be especially deleterious and may lead to secondary damage.The Cockayne syndrome B (CSB) gene is defective in approximately two-thirds of patients with Cockayne syndrome (CS), an autosomal recessive disease with diverse clinical signs including severe growth failure, progressive neurodegeneration, and hypersensitivity to sunlight. CSB has an established role in transcription-coupled nucleotide excision repair (TC-NER) of photo lesions. When RNA POLII is stalled at bulky lesions, CSB is loaded to facilitate NER of the transcribed strand (6, 7). As noted, in addition to UV sensitivity, CS patients also manifest severe neurodegeneration (8, 9), suggesting the importance of CS proteins in maintaining genome stability against a broad spectrum of DNA damage. For example, CSB-defective cells are also sensitive to ionizing radiation (IR) (10, 11), which is phenotypically distinctive from classic NER deficiencies and indicates that CSB function is not limited to UV-derived photo lesions. In addition, CSB-deficient mice exhibit a subset of sy...

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Section: Rna Polymerase II Inhibition Affects the Recruitment Of Hr Fmentioning

confidence: 99%

DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination

Wei

Nakajima

Böhm

et al. 2015

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

131

138

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“…Rad9 is phosphorylated by the ATR ortholog Mec1 and is often referred to as a 53BP1 ortholog, although 53BP1 is dispensable for checkpoint signaling. Nonetheless, like 53BP1, Rad9 limits resection through a mechanism that involves Sgs1 (the only BLM/WRN-like helicase in yeast) and Exo1 (Lydall and Weinert, 1995;Lazzaro et al, 2008;Ngo et al, 2014;Bonetti et al, 2015;Clerici et al, 2014). However, the inhibition of resection by Rad9 does not involve Rif1.…”

Section: Potential Roles For Atr-controlled Resectionmentioning

confidence: 99%

TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres

2017

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SUMMARYThe regulation of 5' end resection at DSBs and telomeres prevents genome instability. DSB resection is positively and negatively regulated by ATM signaling through CtIP/MRN and 53BP1-bound Rif1, respectively. Similarly, telomeres lacking TRF2 undergo ATM-controlled CtIPdependent hyper-resection when the repression by 53BP1/Rif1 is alleviated. However, telomere resection in absence of 53BP1/Rif1 is more extensive upon complete removal of shelterin, indicating additional protection against resection by shelterin. Here we show that TPP1 and POT1a/b in shelterin block a resection pathway distinct from that repressed by TRF2. This second pathway is regulated by ATR signaling, involves Exo1 and BLM, and is inhibited by 53BP1/Rif1. Thus, mammalian cells have two distinct 5' end resection pathways that are regulated by DNA damage signaling, in part through Rif1-mediated inhibition. The data show that telomeres are protected from hyper-resection through the repression of the ATM and ATR kinases by TRF2 and TPP1-bound POT1a/b, respectively.

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“…One of the first events following meiotic DSB formation is MRN/ CtIP-initiated end resection, which promotes homologous recombination and also creates a barrier to error-prone end-joining mechanisms of repair (Joyce et al 2012;Yin and Smolikove 2013). Resection is initiated by MRE11-dependent endonucleolytic incisions near DSBs, followed by bidirectional resection that requires both MRN and EXO1 (Zakharyevich et al 2010;Garcia et al 2011 and the 9-1-1 complex are also required to restrain hyperresection (Shinohara et al 2003;Gray et al 2013;Clerici et al 2014). Given that a number of nucleases are involved in the resection process (Mimitou and Symington 2009;Zakharyevich et al 2010;Garcia et al 2011;Schaetzlein et al 2013), an appealing model is that the MCN ensures appropriate resection rates by activating some nucleases, while (temporarily) inhibiting others (Segurado and Diffley 2008;Manfrini et al 2010;Luo et al 2013;Souquet et al 2013).…”

Section: Control Of Dsb Repair Activation Of Dsb End Processingmentioning

confidence: 99%

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

Subramanian

Hochwagen

2014

Cold Spring Harbor Perspectives in Biology

174

178

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The generation of haploid gametes by meiosis is a highly conserved process for sexually reproducing organisms that, in almost all cases, involves the extensive breakage of chromosomes. These chromosome breaks occur during meiotic prophase and are essential for meiotic recombination as well as the subsequent segregation of homologous chromosomes. However, their formation and repair must be carefully monitored and choreographed with nuclear dynamics and the cell division program to avoid the creation of aberrant chromosomes and defective gametes. It is becoming increasingly clear that an intricate checkpointsignaling network related to the canonical DNA damage response is deeply interwoven with the meiotic program and preserves order during meiotic prophase. This meiotic checkpoint network (MCN) creates a wide range of dependent relationships controlling chromosome movement, chromosome pairing, chromatin structure, and double-strand break (DSB) repair. In this review, we summarize our current understanding of the MCN. We discuss commonalities and differences in different experimental systems, with a particular emphasis on the emerging design principles that control and limit cross talk between signals to ultimately ensure the faithful inheritance of chromosomes by the next generation.

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Mec1/ATR regulates the generation of single-stranded DNA that attenuates Tel1/ATM signaling at DNA ends

Cited by 58 publications

References 66 publications

DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination

DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B-dependent homologous recombination

TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres

The Meiotic Checkpoint Network: Step-by-Step through Meiotic Prophase

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