ATR–ATRIP Kinase Complex Triggers Activation of the Fanconi Anemia DNA Repair Pathway

Shigechi, Tomoko; Tomida, Junya; Sato, Koichi; Kobayashi, Masahiko; Eykelenboom, John K.; Pessina, Fabio; Zhang, Yanbin; Uchida, Emiko; Ishiai, Masamichi; Lowndes, Noel F.; Yamamoto, Kenichi; Kurumizaka, Hitoshi; Maehara, Yoshihiko; Takata, Minoru

doi:10.1158/0008-5472.can-11-2904

Cited by 60 publications

(64 citation statements)

References 35 publications

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“…Atr is activated (phosphorylated) by signaling events triggered by ss/dsDNA hybrids, as found at the site of a stalled or collapsed replication forks (29). Activated Atr induces S phase arrest for replication fork repair and directly activates some Fanconi proteins (27). If repair is not successful, Atr activates a signaling cascade resulting in p53-mediated apoptosis (28, 30).…”

Section: Discussionmentioning

confidence: 99%

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC−/− Mice

Huang

Bei

et al. 2018

The Journal of Immunology

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Emergency (stress) granulopoiesis is an episodic process for production of granulocytes in response to infectious challenge. We previously determined that Fanconi C, a component of the Fanconi DNA-repair pathway, is necessary for successful emergency granulopoiesis. Fanconi Anemia (FA) results from mutation of any gene in this pathway and is characterized by bone marrow failure (BMF) in childhood and clonal progression in adolescence. Although murine FA models exhibit relatively normal steady state hematopoiesis, FANCC−/− mice are unable to mount an emergency granulopoiesis response. Instead, these mice develop BMF and death during repeated, unsuccessful emergency granulopoiesis attempts. In FANCC−/− mice, BMF is associated with extensive apoptosis of hematopoietic stem and progenitor cells through an undefined mechanism. In the current studies, we find TP53 haplo-insufficiency completely rescues emergency granulopoiesis in FANCC−/− mice and protects them from BMF during repeated emergency granulopoiesis episodes. Instead, such recurrent challenges accelerated clonal progression in FANCC−/−TP53+/− mice. In FANCC−/− mice, BMF during multiple emergency granulopoiesis attempts was associated with increasing Atr and p53 activation with each attempt. In contrast, we found progressive attenuation of expression and activity of Atr, and consequent p53 activation and apoptosis, in the bone marrow of FANCC−/−TP53+/− mice during this process. Therefore, activation of Atr, with consequent Fanconi mediated DNA repair or p53-dependent apoptosis, are essential components of emergency granulopoiesis and protect the bone marrow from genotoxic stress during this process.

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Section: Discussionmentioning

confidence: 99%

TP53 Haploinsufficiency Rescues Emergency Granulopoiesis in FANCC−/− Mice

Huang

Bei

et al. 2018

The Journal of Immunology

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“…Furthermore, increasing amounts of RPA-ssDNA is generated at or behind replication forks when the coordination between helicase and DNA polymerases is compromised by DNA damage and other impediments (Byun et al 2005;Lopes et al 2006). The ability of ATR-ATRIP to recognize RPAssDNA gives it its unusual versatility in sensing DNA damage and replication stress Namiki and Zou 2006;Shigechi et al 2012).…”

Section: Dna Damage Sensing Beyond Dna Breaksmentioning

confidence: 99%

DNA Damage Sensing by the ATM and ATR Kinases

Maréchal

Zou

2013

Cold Spring Harbor Perspectives in Biology

1,197

918

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In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrated by the ATM and ATR kinases is the central regulator of this network in response to DNA damage. Both ATM and ATR are activated by DNA damage and DNA replication stress, but their DNAdamage specificities are distinct and their functions are not redundant. Furthermore, ATM and ATR often work together to signal DNA damage and regulate downstream processes. Here, we will discuss the recent findings and current models of how ATM and ATR sense DNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR.

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“…Ubiquitin-specific peptidase 1 (USP1) and the USP1-associated protein (UAF1) regulate deubiquitination of FANCD2/FANCI and are required for completion of the FA pathway (69,70). The ATR/ ATRIP heterodimer is required for sensing single-strand DNA generated during S phase and for the induction of FANCD2/FANCI monoubiquitylation in response to DNA damage (71). Proteins involved in ATR signaling, such as RPA (single-strand DNA binding protein), RAD17, RAD9 (9-1-1 checkpoint complex), CHK1, and HCLK2, are required for the efficient induction of FANCD2/ FANCI monoubiquitylation (36,72).…”

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confidence: 99%