Comparable axon stalling defects of adult MB neurons, as well as missing larval MB dorsal axonal branches were observed in unf mutant organisms (Bates et al., submitted), validating our study of unf's mechanism of action by targeted RNAi.
In this case, the degradation of the defective 18S rRNAs utilizes the same Dom34/ Hbs1 complex that is involved in the release of ribosomes stalled by defects in the mRNA (NGD; see above), which leads to degradation by the cytoplasmic exosome as well as Xrn1 (Cole et al. 2009).
Thus, inadequate handling of stalled forks or defects of DNA replication can lead to accumulation of mutations and genomic aberrations [ 10].
The result was that, by the early nineteen-seventies, American productivity growth was stalling, while American products were often defect-ridden and unreliable.
In vitro, telomeric replication forks are prone to slipping, and replication of telomeric DNA is inefficient and prone to defects consistent with fork stalling.
Wanrooij et al. (41) used two dimensional DNA analysis to show that cells, over-expressing POLG1 or TWINKLE containing catalytic defects, have both cellular depletion of mtDNA and replisome stalling.
In this assay, defects in replication fork progression or elongation can be further exacerbated via stalling the fork using a dose of hydroxyurea (HU, a ribonucleotide reductase inhibitor) that does not cause fork collapse [ 24].
Another, not-mutually exclusive, possibility is that altered chromatin structure increases the steady-state level of DNA damage due to replication defects such as impaired passage of the replication machinery or to replication fork stalling.
Significantly, mutations in genes encoding proteins functioning in the replication fork that frequently cause replication stalling often lead to gross chromosomal rearrangements (GCR), whereas mutations arising as a consequence of polymerase defects are mainly base substitutions and frameshifts.
