A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair

Tomida, Junya; Itaya, Akiko; Shigechi, Tomoko; Unno, Junya; Uchida, Emiko; Ikura, Masae; Masuda, Yuji; Matsuda, Shun; Adachi, Jun; Kobayashi, Masahiko; Meetei, Amom Ruhikanta; Maehara, Yoshihiko; Yamamoto, Ken; Kamiya, Kenji; Matsuura, Akira; Matsuda, Tomonari; Ikura, Tsuyoshi; Ishiai, Masamichi; Takata, Minoru

doi:10.1093/nar/gkt467

Cited by 50 publications

(49 citation statements)

References 62 publications

(66 reference statements)

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“…4,59 Interestingly while MMC elicits the checkpoint, ATR activation is via the Fanconi anemia core complex rather than the canonical pathway involving Rad17. [59][60][61] Thus, our findings raise the possibility that the action of CST is somehow linked to a specific aspect of ATR signaling. We previously showed that STN1 depleted cells exhibit a normal ATR response to HU treatment as the level of Chk1 phosphorylation is similar to that of control cells as is the rate of Chk1 dephosphorylation and loss of RPA foci after HU release.…”

Section: Discussionmentioning

confidence: 70%

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Wang¹,

Stewart

Price³

2014

Cell Cycle

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Mammalian CST (CTC1-STN1-TEN1) is a telomere-associated complex that functions in telomere duplex replication and fill-in synthesis of the telomeric C-strand following telomerase action. CST also facilitates genome-wide replication recovery after HU-induced fork stalling by increasing origin firing. CTC1 and STN1 were originally isolated as a DNA polymerase a stimulatory factor. Here we explore how CST abundance affects recovery from drugs that cause different types of DNA damage and replication stress. We show that recovery from HU and aphidicolin induced replication stress is increased by CST over-expression. Elevated CST increases dNTP incorporation and origin firing after HU release and decreases the incidence of anaphase bridges and micronuclei after aphidicolin removal. While the frequency of origin firing after HU release is proportional to CST abundance, the number of cells entering S-phase to initiate replication is unchanged by CST overexpression or STN1 depletion. Instead the CST-related changes in origin firing take place in cells that were already in S-phase at the time of HU addition, indicating that CST modulates firing of late or dormant origins. CST abundance also influences cell viability after treatment with HU, aphidicolin, MMS and camptothecin. Viability is increased by elevated CST and decreased by STN1 depletion, indicating that endogenous CST levels are limiting. However, CST abundance does not affect viability after MMC treatment. Thus, CST facilitates recovery from many, but not all, forms of exogenous DNA damage. Overall our results suggest that CST is needed in stoichiometric amounts to facilitate re-initiation of DNA replication at repaired forks and/or dormant origins.

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Section: Discussionmentioning

confidence: 70%

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Wang¹,

Stewart

Price³

2014

Cell Cycle

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“…S1C and S4A). Rad17 promotes Chk1 phosphorylation, which is a marker of replication checkpoint activation, in association with Rad9-Rad1-Hus1, TopBP1, and ATR-ATRIP, whereas it does not affect the monoubiquitination of FANCD2 [25,30]. RECQL5 / RAD17 KO cells showed higher sensitivity to CDDP than single mutants (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Tumor suppressor RecQL5 controls recombination induced by DNA crosslinking agents

Hosono

Abe

Ishiai

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RecQ family DNA helicases function in the maintenance of genome stability. Mice deficient in RecQL5, one of five RecQ helicases, show a cancer predisposition phenotype, suggesting that RecQL5 plays a tumor suppressor role. RecQL5 interacts with Rad51, a key factor in homologous recombination (HR), and displaces Rad51 from Rad51-single stranded DNA (ssDNA) filaments in vitro. However, the precise roles of RecQL5 in the cell remain elusive. Here, we present evidence suggesting that RecQL5 is involved in DNA interstrand crosslink (ICL) repair. Chicken DT40 RECQL5 gene knockout (KO) cells showed sensitivity to ICL-inducing agents such as cisplatin (CDDP) and mitomycin C (MMC) and a higher number of chromosome aberrations in the presence of MMC than wild-type cells. The phenotypes of RECQL5 KO cells resembled those of Fanconi anemia gene KO cells. Genetic analysis using corresponding gene knockout cells showed that RecQL5 is involved in the FANCD1 (BRCA2)-dependent ICL repair pathway in which Rad51-ssDNA filament formation is promoted by BRCA2. The disappearance but not appearance of Rad51-foci was delayed in RECQL5 KO cells after MMC treatment. Deletion of Rad54, which processes the Rad51-ssDNA filament in HR, in RECQL5 KO cells increased sensitivity to CDDP and further delayed the disappearance of Rad51-foci, suggesting that RecQL5 and Rad54 have different effects on the Rad51-ssDNA filament. Furthermore, the frequency and variation of CDDP-induced gene conversion at the immunoglobulin locus were increased in RECQL5 KO cells. These results suggest that RecQL5 plays a role in regulating the incidence and quality of ICL-induced recombination.

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“…The recruitment of ATRIP was reported to be essential for FANCD2 monoubiquitination and FANCI phosphorylation, and the latter is catalyzed by ATR kinase [70]. The FA core complex E3 was found to also enhance the binding of ATRIP to the damaged chromatin site [71]. Together, FANCM, FANCW and other FA players certainly play critical roles in the sensor phase upon stalled replication forks.…”

Section: Fa Signaling and Master Regulators Of Cellular Stress Rementioning

confidence: 99%

Fanconi Anemia Signaling and Cancer

et al. 2017

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The extremely high cancer incidence associated with patients suffering from a rare human genetic disease, Fanconi Anemia (FA), demonstrates the importance of FA genes. Over the course of human tumor development, FA genes perform critical tumor-suppression roles. In doing so, FA provides researchers with a unique genetic model system to study cancer etiology. Here, we review how aberrant function of the twenty-two FA genes and their signaling network contributes to malignancy. From this perspective, we will also discuss how the knowledge discovered from FA research serves basic and translational cancer research.

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A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair

Cited by 50 publications

References 62 publications

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Human CST abundance determines recovery from diverse forms of DNA damage and replication stress

Tumor suppressor RecQL5 controls recombination induced by DNA crosslinking agents

Fanconi Anemia Signaling and Cancer

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