Fanconi anemia signaling network regulates the spindle assembly checkpoint

Nalepa, Grzegorz; Enzor, Rikki; Sun, Zejin; Marchal, Christophe; Park, Su Jung; Yang, Yanzhu; Tedeschi, Laura; Kelich, Stephanie L.; Hanenberg, Helmut; Clapp, D. Wade

doi:10.1172/jci67364

Cited by 59 publications

(89 citation statements)

References 43 publications

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“…i) Recent studies have shown that several DNA repair proteins localize to the centrosome, and defects in these proteins cause several functional aberrations in centrosomes such as centrosome amplification. [40][41][42][43] Also, it has been shown that DNA damage can induce centrosome amplification. [41][42][43] Overexpression of Usp1 in NIH3T3 cells inhibited UV-induced Fancd2-Ub and PCNA-Ub (Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

2016

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Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting chromosome missegregation. Therefore, maintenance of accurate centrosome number is critical for cell fate. The deubiquitinating enzyme USP1 plays important roles in DNA repair and cell differentiation. Importantly, increased levels of USP1 are detected in certain types of human cancer, but little is known about the significance of USP1 overexpression in cancer development. Here we show that Usp1 plays a novel role in regulating centrosome duplication. The ectopic expression of wild-type Usp1, but not C90S Usp1 (catalytically inactive mutant form), induced centrosome amplification. Conversely, ablation of Usp1 in mouse embryonic fibroblasts (MEFs) showed a significant delay in centrosome duplication. Moreover, Usp1-induced centrosome amplification caused abnormal mitotic spindles, chromosome missegregation and aneuploidy. Interestingly, loss of inhibitor of DNA binding protein 1 (ID1) suppressed Usp1-induced centrosome amplification. Taken together, our results strongly suggest that Usp1 is involved in the regulation of centrosome duplication, at least in part via ID1, and Usp1 may exert its oncogenic activity, partially through inducing centrosome abnormality.

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Section: Discussionmentioning

confidence: 99%

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

2016

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“…In addition, several FA proteins localize to centrosomes and the mitotic spindle. 98,101 DNA damage response and FA: ATM, ATR, and CHK1…”

Section: Fa Pathway and Cytokinesismentioning

confidence: 99%

Stress and DNA repair biology of the Fanconi anemia pathway

Longerich

Xiong

et al. 2014

Blood

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Fanconi anemia (FA) represents a paradigm of rare genetic diseases, where the quest for cause and cure has led to seminal discoveries in cancer biology. Although a total of 16 FA genes have been identified thus far, the biochemical function of many of the FA proteins remains to be elucidated. FA is rare, yet the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. Importantly, recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. Moreover, despite improved outcomes in stem cell transplantation in the treatment of FA, many challenges remain in patient care. (Blood.

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“…Consistent with our findings, Nalepa and colleagues also observed a higher percentage of fibroblast cells taken from FA patients including FancJ patients showing centrosome amplification compared to that from healthy individuals. 40 Though the exact physiological implication is still unknown, DDICA is thought to be another fail-safe mechanism to commit cells experiencing severe DNA damages to cell death and thereby plays a potential role in suppressing tumorigenesis. 10 Here we showed that deficiency of BRCA1 induces centrosome amplification in non-stressed cells as previously reported while attenuating both HU-and MMC-induced centrosome amplification.…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1

et al. 2014

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DNA damage response (DDR) and the centrosome cycle are 2 of the most critical cellular processes affecting the genome stability in animal cells. Yet the cross-talks between DDR and the centrosome are poorly understood. Here we showed that deficiency of the breast cancer 1, early onset gene (BRCA1) induces centrosome amplification in nonstressed cells as previously reported while attenuating DNA damage-induced centrosome amplification (DDICA) in cells experiencing prolonged genotoxic stress. Mechanistically, the function of BRCA1 in promoting DDICA is through binding and recruiting polo-like kinase 1 (PLK1) to the centrosome. In a recent study, we showed that FancJ also suppresses centrosome amplification in non-stressed cells while promoting DDICA in both hydroxyurea and mitomycin C treated cells. FancJ is a key component of the BRCA1 B-complex. Here, we further demonstrated that, in coordination with BRCA1, FancJ promotes DDICA by recruiting both BRCA1 and PLK1 to the centrosome in the DNA damaged cells. Thus, we have uncovered a novel role of BRCA1 and FancJ in the regulation of DDICA. Dysregulation of DDR or centrosome cycle leads to aneuploidy, which is frequently seen in both solid and hematological cancers. BRCA1 and FancJ are known tumor suppressors and have well-recognized functions in DNA damage checkpoint and DNA repair. Together with our recent findings, we demonstrated here that BRCA1 and FancJ also play an important role in centrosome cycle especially in DDICA. DDICA is thought to be an alternative fail-safe mechanism to prevent cells experiencing severe DNA damage from becoming carcinogenic. Therefore, BRCA1 and FancJ are potential liaisons linking early DDR with the DDICA. We propose that together with their functions in DDR, the role of BRCA1 and FancJ in the activation of DDICA is also crucial for their tumor suppression functions in vivo.

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Fanconi anemia signaling network regulates the spindle assembly checkpoint

Cited by 59 publications

References 43 publications

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

Stress and DNA repair biology of the Fanconi anemia pathway

BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1

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