Cryptic unstable transcript

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Cryptic unstable transcripts (CUTs) are short, non-coding RNAs produced by RNA Polymerase II from intergenic and intragenic regions in yeast and other eukaryotes. They are usually about 200–800 bases long, have a 5′ cap and a poly-A tail, and are degraded quickly, so they’re typically hard to detect under normal conditions. CUTs often start in nucleosome-free promoter areas and can be antisense to nearby genes.

Discovery and characterization
- Early studies in S. cerevisiae using tiling arrays showed widespread transcription in intergenic regions.
- CUTs are rapidly degraded in the nucleus and cytoplasm, so they accumulate mainly when decay pathways are impaired (for example, in exosome mutants like Δrrp6).
- In 2009, researchers mapped non-coding transcripts and found CUTs account for a notable fraction of transcripts (roughly 13%).

Degradation pathways
- CUTs are kept at low levels by two main decay routes:
- The Nrd1–Nab3–Sen1 pathway, which recruits the nuclear exosome (including Rrp6) with help from the TRAMP complex that adds poly(A) tails to mark transcripts for degradation.
- Termination and polyadenylation activities that can lead to decay, plus 5′-to-3′ decay enzymes.
- Cytoplasmic decay also involves the decapping enzymes (Dcp1/Dcp2) and the exonuclease Xrn1.
- SUTs (stable uncharacterized transcripts) resemble CUTs but are only partially degraded by the exosome and are degraded largely by Dcp1/Dcp2 and Xrn1.

The Nrd1–Nab3–Sen1 and TRAMP pathway
- Nrd1 and Nab3 recognize specific RNA motifs; Sen1 helps unwind RNA.
- They recruit the nuclear exosome (with Rrp6) to degrade CUTs.
- TRAMP (Trf4/Trf5 with Air1/Air2 and Mtr4) polyadenylates and marks CUTs for degradation, functioning alongside Pap1p in some contexts.

Role of Xrn1
- Xrn1, in the cytoplasm, helps degrade decapped CUTs after removal of the 5′ cap.
- This pathway also participates in controlling SUT levels.

Relation with bidirectional promoters
- CUTs often originate from promoters that drive transcription in both directions (bidirectional promoters).
- The ends of CUTs frequently sit near the start sites of protein-coding genes, in both sense and antisense orientations.
- Sense CUTs are more common near promoters of glucose metabolism genes; antisense CUTs are widely distributed.

SUTs
- Stable uncharacterized transcripts (SUTs) are similar to CUTs in origin and non-coding nature.
- SUTs can be detected in wild-type cells and in exosome mutants, indicating partial exosome degradation.
- They are mainly degraded by Dcp1, Dcp2, and Xrn1, and some SUTs participate in gene silencing or trans-silencing activities (e.g., affecting TY1 retrotransposons).

Interaction with histones
- Chromatin state influences CUT production. For example:
- Set2-dependent histone H3K36 methylation helps suppress intragenic CUTs; loss of Set2 leads to more exon-derived CUTs.
- Proper nucleosome distribution (involving Spt6/Spt16) prevents unintended transcription; defects increase CUT formation.
- CUTs can affect promoter accessibility and gene expression by influencing histone modifiers.

Histone eviction and CUTs
- A CUT at the PHO5 promoter speeds up promoter remodeling, suggesting CUTs can help modulate chromatin openness.
- In some mutant cells, antisense transcripts recruit histone deacetylases to silence nearby genes (e.g., PHO84), linking CUTs to chromatin-based regulation.

PROMPTs
- PROMPTs are promoter upstream transcripts found around 1–1.5 kb upstream of human transcription start sites in non-genic regions.
- Like CUTs, PROMPTs are detected when the exosome is inhibited and can be sense or antisense.
- They’re thought to help explain parts of the non-coding transcript landscape and may have regulatory roles.

Function
- CUTs and SUTs may regulate genes and chromatin states, even in the absence of an RNAi system (as in yeast).
- Examples of regulatory roles include:
- Antisense transcripts that recruit histone deacetylases to silence genes (e.g., PHO84).
- Trans-silencing effects on transposable elements (e.g., TY1) in yeast.
- Noncoding transcripts that influence promoter accessibility and transcription initiation (e.g., PHO5, SER3).

See also
- Non-coding RNA

Bottom line
- CUTs are widespread, short, rapidly degraded non-coding RNAs that originate mainly from promoters and other regulatory regions.
- They are controlled by multiple RNA decay pathways and chromatin-related processes, and they likely play important, nuanced roles in regulating gene expression and genome architecture.