Cyclin F-Mediated Degradation of Ribonucleotide Reductase M2 Controls Genome Integrity and DNA Repair

D’Angiolella, Vincenzo; Donato, Valerio; Forrester, Frances M.; Jeong, Yeong-Ho; Pellacani, Claudia; Kudo, Yasusei; Saraf, Anita; Florens, Laurence; Washburn, Michael P.; Pagano, Michele

doi:10.1016/j.cell.2012.03.043

Cited by 321 publications

(414 citation statements)

References 64 publications

Supporting

Mentioning

384

Contrasting

Order By: Relevance

“…Previous work has demonstrated transcriptome changes in Pax3 þ satellite cells population (from abdominal muscles) in response to injury [47], and in conjunction with this data, our analyses could be used to define the different responses of muscle to chronic (e.g., in dystrophic muscle) or acute (cardiotoxintreated) injury as well as the responses of different satellite cell populations. The presence of known regeneration factors such as the DNA synthesis-associated gene Rrm2 [58] in the upregulated gene list suggests the usefulness of our data to identify novel regeneration markers and regulators of satellite cell function. Regeneration in the absence of p38a revealed markedly different gene expression compared with that of the p38a fl satellite cells.…”

Section: Discussionmentioning

confidence: 99%

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

et al. 2013

View full text Add to dashboard Cite

Stem cell function is essential for the maintenance of adult tissue homeostasis. Controlling the balance between selfrenewal and differentiation is crucial to maintain a receptive satellite cell pool capable of responding to growth and regeneration cues. The mitogen-activated protein kinase p38a has been implicated in the regulation of these processes but its influence in adult muscle remains unknown. Using conditional satellite cell p38a knockout mice we have demonstrated that p38a restricts excess proliferation in the postnatal growth phase while promoting timely myoblast differentiation. Differentiation was still able to occur in the p38a-null satellite cells, however, but was delayed. An absence of p38a resulted in a postnatal growth defect along with the persistence of an increased reservoir of satellite cells into adulthood. This population was still capable of responding to cardiotoxin-induced injury, resulting in complete, albeit delayed, regeneration, with further enhancement of the satellite cell population. Increased p38c phosphorylation accompanied the absence of p38a, and inhibition of p38c ex vivo substantially decreased the myogenic defect. We have used genomewide transcriptome analysis to characterize the changes in expression that occur between resting and regenerating muscle, and the influence p38a has on these expression profiles. This study provides novel evidence for the fundamental role of p38a in adult muscle homeostasis in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

et al. 2013

View full text Add to dashboard Cite

show abstract

“…During S-phase, the pools expand due to the induction of ribonucleotide reductase (RNR), the major anabolic enzyme providing deoxynucleotides for DNA replication. Outside S-phase, RNR activity is restricted by the ubiquitin-dependent degradation of its R2 subunit [11,12], with concomitant contraction of dNTP pools. In G1 and in quiescent cells, p53R2, the stable small subunit of RNR, provides dNTPs for DNA repair and mitochondrial DNA maintenance [13].…”

Section: Introductionmentioning

confidence: 99%

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

et al. 2018

View full text Add to dashboard Cite

SAMHD1 is the major catabolic enzyme regulating the intracellular concentrations of DNA precursors (dNTPs). The S-phase kinase CDK2-cyclinA phosphorylates SAMHD1 at Thr-592. How this modification affects SAMHD1 function is highly debated. We investigated the role of endogenous SAMHD1 phosphorylation during the cell cycle. Thr-592 phosphorylation occurs first at the G1/S border and is removed during mitotic exit parallel with Thr-phosphorylations of most CDK1 targets. Differential sensitivity to the phosphatase inhibitor okadaic acid suggested different involvement of the PP1 and PP2 families dependent upon the time of the cell cycle. SAMHD1 turn-over indicates that Thr-592 phosphorylation does not cause rapid protein degradation. Furthermore, SAMHD1 influenced the size of the four dNTP pools independently of its phosphorylation. Our findings reveal that SAMHD1 is active during the entire cell cycle and performs an important regulatory role during S-phase by contributing with ribonucleotide reductase to maintain dNTP pool balance for proper DNA replication.

show abstract

“…F‐box proteins can function as tumor suppressor or oncogenes and have been implicated in the control of cell proliferation and cancer development (D'Angiolella et al , 2012; Bassermann et al , 2014). Novel compounds targeting F‐box proteins have been developed, and therefore, F‐box proteins represent candidate pharmacological targets to treat cancer (Skaar et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

Self Cite

View full text Add to dashboard Cite

Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

show abstract

Cyclin F-Mediated Degradation of Ribonucleotide Reductase M2 Controls Genome Integrity and DNA Repair

Cited by 321 publications

References 64 publications

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Contact Info

Product

Resources

About