Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0004135 (
ATM
)
13,001
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The tumor suppressor
F-box protein 31
(
FBXO31
) is indispensable for maintaining genomic stability. Its levels drastically increase following DNA damage, leading to cyclin D1 and MDM2 degradation and G
1
and G
2
/M arrest. Prolonged arrest in these phases leads to cellular senescence. Accordingly,
FBXO31
needs to be kept at low basal levels in unstressed conditions for normal cell cycle progression during growth and development. However, the molecular mechanism maintaining these basal
FBXO31
levels has remained unclear. Here, we identified the F-box family SCF-E3 ubiquitin ligase FBXO46 (SCF
FBXO46
) as an important proteasomal regulator of
FBXO31
and found that FBXO46 helps maintain basal
FBXO31
levels under unstressed conditions and thereby prevents premature senescence. Using molecular docking and mutational studies, we showed that FBXO46 recognizes an R
XX
R motif located at the
FBXO31
C terminus to direct its polyubiquitination and thereby proteasomal degradation. Furthermore, FBXO46 depletion enhanced the basal levels of
FBXO31
, resulting in senescence induction. In response to genotoxic stress,
ATM
(
ataxia telangiectasia
-mutated) Ser/Thr kinase-mediated phosphorylation of
FBXO31
at Ser-278 maintained
FBXO31
levels. In contrast, activated
ATM
phosphorylated FBXO46 at Ser-21/Ser-67, leading to its degradation via
FBXO31
. Thus,
ATM
-catalyzed phosphorylation after DNA damage governs
FBXO31
levels and FBXO46 degradation via a negative feedback loop. Collectively, our findings reveal that FBXO46 is a crucial proteasomal regulator of
FBXO31
and thereby prevents senescence in normal growth conditions. They further indicate that FBXO46-mediated regulation of
FBXO31
is abrogated following genotoxic stress to promote increased
FBXO31
levels for maintenance of genomic stability.
...
PMID:The SCF
FBXO46
ubiquitin ligase complex mediates degradation of the tumor suppressor FBXO31 and thereby prevents premature cellular senescence. 3017 Oct 69
