7 research outputs found
ARF stimulates XPC to trigger nucleotide excision repair by regulating the repressor complex of E2F4
The tumour suppressor ARF (alternative reading frame), which is mutated or silenced in various tumours, has a crucial role in tumour surveillance to suppress unwarranted cell growth and proliferation. ARF has also been linked to the DNA-damage-induced response of p53 because of its ability to inhibit murine double minute 2 (MDM2). Here, however, we provide genetic evidence for a role of ARF in nucleotide excision repair (NER) that is independent of p53. Cells lacking ARF are deficient in NER. Expression of ARF restores the repair activity, which coincides with increased expression of the damaged-DNA recognition protein xeroderma pigmentosum, complementation group C (XPC). We provide evidence that, by disrupting the interaction between E2F transcription factor 4 (E2F4) and DRTF polypeptide 1 (DP1), ARF reduces the interaction of the E2F4–p130 repressor complex with the promoter of XPC to ensure high-level expression of XPC. Together, our results point to an important ‘care-taker'-type tumour-suppression function for ARF in NER through the increased expression of XPC
A Regulatory Role of the Bateman Domain of IMP Dehydrogenase in Adenylate Nucleotide Biosynthesis*
The Bateman domain (CBS subdomain) of IMP dehydrogenase (IMPDH), a
rate-limiting enzyme of the de novo GMP biosynthesis, is
evolutionarily conserved but has no established function. Deletion of the
Bateman domain has no effect on the in vitro IMPDH activity. We
report that in vivo deletion of the Bateman domain of IMPDH in
Escherichia coli (guaBΔCBS) sensitizes the
bacterium to growth arrest by adenosine and inosine. These nucleosides exert
their growth inhibitory effect via a dramatic increase in the intracellular
adenylate nucleotide pool, which results in the enhanced allosteric inhibition
of PRPP synthetase and consequently a PRPP deficit. The ensuing starvation for
pyrimidine nucleotides culminates in growth arrest. Thus, deletion of the
Bateman domain of IMPDH derepresses the synthesis of AMP from IMP. The growth
inhibitory effect of inosine can be rescued by second-site suppressor
mutations in the genes responsible for the conversion of inosine to AMP
(gsk, purA, and purB) as well as by the
prsA1 allele, which encodes a PRPP synthetase that is insensitive to
allosteric inhibition by adenylate nucleotides. Importantly, the
guaBΔCBS phenotype can be complemented in
trans by a mutant guaB allele, which encodes a catalytically disabled
IMPDHC305A protein containing an intact Bateman domain. We conclude
that the Bateman domain of IMPDH is a negative trans-regulator of adenylate
nucleotide synthesis, and that this role is independent of the catalytic
function of IMPDH in the de novo GMP biosynthesis