DEF1 transcription-coupled nucleotide-excision repair

[Antonialock]

yeast DEF1 is currently annotated to transcription-coupled nucleotide-excision repair.

However, pmid:23993092 "Like DNA replication, transcription is severely affected by DNA damage, with various DNA lesions resulting in RNAPII stalling, pausing, arrest, and/or backtracking (hereafter collectively referred to as transcription stress). It is therefore not surprising that cells have evolved a number of mechanisms to ensure that transcription can rapidly resume upon DNA damage. One important mechanism is transcription-coupled nucleotide excision repair (TC-NER), which removes transcription-blocking lesions so that RNAPII can continue. In budding yeast, TC-NER is dependent on Rad26, the homolog of human Cockayne syndrome B. Intriguingly, Rad26 interacts with another protein, Def1. The phenotypes of cells lacking DEF1 indicate a role for this factor in the DNA damage response, but Def1 is not involved in repair. Instead, it is required for a ‘‘mechanism of last resort.’’ During this alternative process, the largest subunit of RNAPII, Rpb1, becomes ubiquitylated and degraded, which results in disassembly of the large RNAPII complex and allows the lesion to be dealt with by other means. Although it was originally identified as a response to DNA damage it is now known that Rpb1 ubiquitylation and degradation occurs under a number of conditions that result in transcription stress. Together, these mechanisms facilitate nuclear accumulation of a proteasome processed version of Def1, which then acts as a bridging factor between RNAPII and the Elongin-Cullin complex, triggering Rpb1polyubiquitylation."

Also pmid:35633597 Here we show that following UV-irradiation, human Ubiquitin-associated protein 2 (UBAP2) or its paralogue UBAP2-like (UBAP2L) are involved in the ubiquitylation and degradation of RNAPII through the recruitment of Elongin-Cul5 ubiquitin ligase. Together, our data indicate that UBAP2 and UBAP2L are the human orthologues of yeast Def1, and so identify the key missing proteins in the human last resort pathway.

So it looks like the "transcription-coupled nucleotide-excision repair" needs updating? I am not sure to what

positive regulation of proteasomal ubiquitin-dependent protein catabolic process + has_input rpb1? + regulation of DNA repair? Regulation of postreplication repair? (TC-NER is not a child of postreplication repair)

It seems like there are a number of pathways under the "last resort" umbrella so I couldn't specifically state +ve regulation of some DNA repair pathway.

Anything else?

not sure who to tag for input but: @ValWood @srengel

[ValWood]

I think I would have annotated to:

MF has_input rpb1 part_of "proteasomal ubiquitin-dependent protein catabolic process" part of "negative regulation of transcription by polymerase II" during "cellular response to DNA damage stimulus"

I have never found a none clunky way to do these because you need to reference the catabolism, and the pathway being regulated. It is one of the questions I want to ask...

[Antonialock]

ok, I don't think it's part of "negative regulation of transcription by polymerase II" - since the ribosome has stalled it's neg reg of TC-NER?

[ValWood]

Good point (I am reading polymerase for ribosome ;) Maybe only MF has_input rpb1 part_of "proteasomal ubiquitin-dependent protein catabolic process" during "cellular response to DNA damage stimulus"

How are elongin and cul5 annotated?

[ValWood]

Actually that wont help will it. They are core transcription.