RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress

Kanu, Nnennaya; T, Zhang; Burrell, Rebecca A.; Chakraborty, Arindam; Cronshaw, Janet M.; Costa, Clive Da; Grönroos, Eva; Pemberton, Helen; Anderton, Emma; Gonzalez, Leticia; Sabbioneda, Simone; Ulrich, Helle D.; Swanton, Charles; Behrens, Axel

doi:10.1038/onc.2015.427

Cited by 44 publications

(55 citation statements)

References 48 publications

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“…Ubiquitinated PCNA recruits WRNIP protein, which in turn binds to the ATM activating cofactor ATMIN. This pathway is important for coordinating replication completion with cell cycle progression and, in its absence, cells enter mitosis with under-replicated DNA (Kanu et al, 2016). Finally, recent genetic experiments in yeast suggest a role for PCNA ubiquitination and TLS in Okazaki fragment maturation, at least in the context of FEN1 inactivation (Becker et al, 2015).…”

Section: Translesion Synthesismentioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

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Proliferating Cell Nuclear Antigen (PCNA) lies at the center of the faithful duplication of eukaryotic genomes. With its distinctive doughnut-shaped molecular structure, PCNA was originally studied for its role in stimulating DNA polymerases. However, we now know that PCNA does much more than promote processive DNA synthesis. Because of the complexity of the events involved, cellular DNA replication poses major threats to genomic integrity. Whatever predicament lies ahead for the replication fork, PCNA is there to orchestrate the events necessary to handle it. Through its many protein interactions and various post-translational modifications, PCNA has far-reaching impacts on a myriad of cellular functions.

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Section: Translesion Synthesismentioning

confidence: 99%

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

2017

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“…In addition, WRNIP1 D37A cannot form nuclear foci after UVC irradiation nor accumulate at laser-irradiated sites. Because ubiquitylated PCNA is bound by WRNIP1, 21 it may be one of the targets of the WRNIP1 UBZ domain upon UVC or laser light irradiation.…”

Section: The Wrnip1 Gene and Structure Of The Wrnip1 Proteinmentioning

confidence: 99%

“…WRNIP1 interacts with multiple proteins involved in various cellular pathways; these include FGFR1OP (fibroblast growth factor receptor 1 oncogene partner), 28 Nup107, 29 p97/VCP, 30 RAD18, 22 ubiquitylated PCNA, 21 DNA polymerase δ, 3 DNA polymerase η, 31,32 RAD51, BRCA2, 33 ATMIN, 21 and WRN 2 . In this section, we focus on the WRNIP1-interacting proteins involved in DNA replication and/or repair: WRN, RAD18, DNA polymerase δ, and DNA polymerase η.…”

Section: Wrnip1-interacting Proteinsmentioning

confidence: 99%

“…The contribution of ATMIN (ATM interactor) to ATM activation is complementary to that of NBS1, i.e., it is dispensable for IR-induced ATM activation 42 . ATMIN is required for ATM-mediated signaling and recruitment of 53BP1 to DNA damage sites upon replication stress 43 Moreover, WRNIP1 binds ATMIN and facilitates its ATM-activating function 21 . Upon induction of replication stress by aphidicolin, WRNIP1 interacts with monoubiquitylated PCNA and forms foci, dependent upon ubiquitylation of PCNA by RAD18.…”

Section: Functions Of Wrnip1 In Dna Transactionsmentioning

confidence: 99%

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The role of WRNIP1 in genome maintenance

2017

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WRNIP1 interacts with WRN helicase, which is defective in the premature aging disease Werner syndrome. WRNIP1 belongs to the AAA+ ATPase family and is conserved from Escherichia coli to human. The protein contains an ubiquitin-binding zinc finger (UBZ) domain at the N terminus and an ATPase domain in the middle region. In addition to WRN, WRNIP1 interacts with proteins involved in multiple cellular pathways, including RAD18, monoubiquitylated PCNA, DNA polymerase δ, RAD51, and ATMIN. Mgs1, the yeast homolog of WRNIP1, may act downstream of ubiquitylation of PCNA to mobilize DNA polymerase δ. By contrast, the functions of WRNIP1 in higher eukaryotic cells remain obscure, although data regarding the roles of WRNIP1 in DNA transactions have emerged recently. Here, we first describe the functions of Mgs1 in DNA transaction. We then describe various features of WRNIP1 and discuss its possible roles based on recent studies of the function of WRNIP1.

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“…4 ATMIN has a complementary function to NBS1: NBS1 is required for ionizing radiation-induced ATM signaling, whereas ATMIN is required for ATM activation after hypotonic or replication stress. 3,5,6 ATMIN has been shown to function in conditions of oxidative stress and aging 7 and as a transcription factor. 8 We have previously shown that ATMIN-deleted B cells (induced by CD19-Cre) have impaired class switch recombination and increased genomic instability, leading to B-cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

Perturbed hematopoiesis in mice lacking ATMIN

Anjos-Afonso

Loizou

Bradburn

et al. 2016

Blood

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Key Points• ATMIN deletion using Vav-Cre causes chronic leukopenia, with fewer B cells and common myeloid progenitors.• Long-term HSCs in ATMINdeficient mice show increased cell cycling and are more prone to exhaustion under stress.The ataxia telangiectasia mutated (ATM)-interacting protein ATMIN mediates noncanonical ATM signaling in response to oxidative and replicative stress conditions. Like ATM, ATMIN can function as a tumor suppressor in the hematopoietic system: deletion of Atmin under the control of CD19-Cre results in B-cell lymphomas in aging mice. ATM signaling is essential for lymphopoiesis and hematopoietic stem cell (HSC) function; however, little is known about the role of ATMIN in hematopoiesis. We thus sought to investigate whether the absence of ATMIN would affect primitive hematopoietic cells in an ATM-dependent or -independent manner. Apart from its role in B-cell development, we show that ATMIN has an ATM-independent function in the common myeloid progenitors (CMPs) by deletion of Atmin in the entire hematopoietic system using Vav-Cre. Despite the lack of lymphoma formation, ATMIN-deficient mice developed chronic leukopenia as a result of high levels of apoptosis in B cells and CMPs and induced a compensatory mechanism in which HSCs displayed enhanced cycling. Consequently, ATMIN-deficient HSCs showed impaired regeneration ability with the induction of the DNA oxidative stress response, especially when aged. ATMIN, therefore, has multiple roles in different cell types, and its absence results in perturbed hematopoiesis, especially during stress conditions and aging. (Blood. 2016;128(16):2017-2021

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RAD18, WRNIP1 and ATMIN promote ATM signalling in response to replication stress

Cited by 44 publications

References 48 publications

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

The role of WRNIP1 in genome maintenance

Perturbed hematopoiesis in mice lacking ATMIN

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