TopBP1 and DNA polymerase-α directly recruit the 9-1-1 complex to stalled DNA replication forks

Shan, Yan Shen; Michael, W. Matthew

doi:10.1083/jcb.200810185

Cited by 100 publications

(160 citation statements)

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“…Studies using yeast and DT40 cells indicate that PCNA ubiquitination and pol are not required for ongoing replicon movement in UV-irradiated cells but instead play an important role in preventing accumulation of ssDNA gaps behind the replication fork (45,46). Details of the putative re-priming mechanism that maintains leading strand synthesis on damaged templates are not well understood (47). Nevertheless, if the basic mechanisms of TLS are conserved in yeast, chicken (DT40), and mammalian cells and if TLS does indeed occur post-replicatively, it appears likely that Rad18-dependent activation of FA pathway is initiated behind re-primed replication forks.…”

Section: Discussionmentioning

confidence: 99%

Rad18-mediated Translesion Synthesis of Bulky DNA Adducts Is Coupled to Activation of the Fanconi Anemia DNA Repair Pathway

Song

Palle

Gurkar

et al. 2010

Journal of Biological Chemistry

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Fanconi anemia (FA) is a cancer susceptibility syndrome characterized by sensitivity to DNA-damaging agents. The FA proteins (FANCs) are implicated in DNA repair, although the precise mechanisms by which FANCs process DNA lesions are not fully understood. An epistatic relationship between the FA pathway and translesion synthesis (TLS, a post-replication DNA repair mechanism) has been suggested, but the basis for crosstalk between the FA and TLS pathways is poorly understood. We show here that ectopic overexpression of the E3 ubiquitin ligase Rad18 (a central regulator of TLS) induces DNA damage-independent mono-ubiquitination of proliferating cell nuclear antigen (PCNA) (a known Rad18 substrate) and FANCD2. Conversely, DNA damage-induced mono-ubiquitination of both PCNA and FANCD2 is attenuated in Rad18-deficient cells, demonstrating that Rad18 contributes to activation of the FA pathway. WT Rad18 but not an E3 ubiquitin ligase-deficient Rad18 C28F mutant fully complements both PCNA ubiquitination and FANCD2 activation in Rad18-depleted cells. Rad18-induced mono-ubiquitination of FANCD2 is not observed in FA core complex-deficient cells, demonstrating that Rad18 E3 ligase activity alone is insufficient for FANCD2 ubiquitylation. Instead, Rad18 promotes FA core complex-dependent FANCD2 ubiquitination in a manner that is secondary to PCNA monoubiquitination. Taken together, these results demonstrate a novel Rad18-dependent mechanism that couples activation of the FA pathway with TLS.

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Section: Discussionmentioning

confidence: 99%

Rad18-mediated Translesion Synthesis of Bulky DNA Adducts Is Coupled to Activation of the Fanconi Anemia DNA Repair Pathway

Song

Palle

Gurkar

et al. 2010

Journal of Biological Chemistry

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“…A fourth ATR regulator, the MRE11-RAD50-NBS1 (MRN) complex, acts at ssDNA/dsDNA junctions in Xenopus extracts and binds RPA-ssDNA in human cells (Olson et al 2007b;Oakley et al 2009;Duursma et al 2013;Shiotani et al 2013). Both 9-1-1 and MRN interact with TopBP1, an activator of ATR-ATRIP, enabling it to stimulate the ATR kinase on DNA (Kumagai et al 2006;Delacroix et al 2007;Mordes et al 2008;Yan and Michael 2009;Dunphy 2010, 2013;Liu et al 2011;Duursma et al 2013). Through a process that is still not fully elucidated, activated ATR recognizes Chk1 with the help of mediators (e.g., Claspin, Timeless, and Tipin), allowing activation of the ATR-Chk1 kinase cascade (Kumagai and Dunphy 2003;Kumagai et al 2004;UnsalKac xmaz et al 2005UnsalKac xmaz et al , 2007Chou and Elledge 2006;Wang et al 2006;Smith et al 2009).…”

mentioning

confidence: 99%

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

Ouyang

Mori

et al. 2014

Genes Dev.

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The ATR (ATM [ataxia telangiectasia-mutated]-and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR-Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11-RAD50-NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway.[Keywords: ATR; ATRIP; checkpoint; SUMOylation] Supplemental material is available for this article.Received January 18, 2014; revised version accepted June 2, 2014.The maintenance of genomic stability requires not only DNA repair machineries but also signal transduction pathways that regulate and coordinate the DNA damage response (DDR) (Ciccia and Elledge 2010). In human cells, DNA damage signaling is primarily initiated by the ataxia telangiectasia-mutated (ATM) and the ATMand Rad3-related (ATR) kinases. Whereas ATM is activated by DNA double-stranded breaks (DSBs), ATR is elicited by a much broader spectrum of DNA damage and replication stress (Cimprich and Cortez 2008;Marechal and Zou 2013;Shiloh and Ziv 2013). Once activated, ATM and ATR phosphorylate and activate their effector kinases, Chk2 and Chk1, respectively. Together, the ATMChk2 and ATR-Chk1 kinase cascades phosphorylate a number of substrates involved in DNA repair, DNA replication, and cell cycle transitions, coordinating these processes to suppress genomic instability. In addition to the phosphorylation events mediated by the ATM and ATR pathways, several other types of post-translational modifications (PTMs), such as ubiquitylation, SUMOylation, methylation, acetylation, and poly-ADP ribosylation, are also implicated in the DDR (Bekker-Jensen and Mailand 2010;Huen et al. 2010;Lukas et al. 2011;Jackson and Durocher 2013). We recently found that the efficient activation of ATR relies on a ubiquitylation circuitry mediated by RPA-ssDNA (RPA-coated ssDNA) and PRP19 (Marechal et al. 2014). This new finding raises a question as to whether other PTMs also participate in DNA damage signaling through the ATR path...

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“…36,37 Somewhat contradictory, TopBP1 has been shown to localize to stalled replication forks independently of the 9-1-1 complex, and rather be responsible for recruitment of 9-1-1. 38,39 In line with this, recruitment of TopBP1 to ATR activating DNA structures in Xenopus extracts was shown to rely on the MRN complex. The MRN-mediated recruitment seemed to depend on TopBP1 BRCT3-6.…”

Section: Topbp1 Is Required For Atr Activationmentioning

confidence: 75%

TopBP1-mediated DNA processing during mitosis

et al. 2016

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TopBP1 and DNA polymerase-α directly recruit the 9-1-1 complex to stalled DNA replication forks

Cited by 100 publications

References 49 publications

Rad18-mediated Translesion Synthesis of Bulky DNA Adducts Is Coupled to Activation of the Fanconi Anemia DNA Repair Pathway

Rad18-mediated Translesion Synthesis of Bulky DNA Adducts Is Coupled to Activation of the Fanconi Anemia DNA Repair Pathway

SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway

TopBP1-mediated DNA processing during mitosis

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