This is the summative coursework for 4bby1013 Biochemistry, which is based on summarising an article named "The multiple roles of transcription/repair factor TFIIH". I received 82% on this coursework.
Svejstrup JQ, Vichi P, Egly JM. The multiple roles of
transcription/repair factor TFIIH. Trends Biochem Sci. 1996
Sep;21(9):346-50
TFIIH (transcription factor IIH) is a complex multifunctional protein critical for the function of RNA
polymerase II during transcription, nucleotide excision repair (NER) and cell cycle regulation.
TFIIH is composed of several subunits, mainly XPB and XPD, which are critical to the function of TFIIH.
The two DNA helicases encoded by the genes XPB and XPD in humans (SsI2 and Rad3 in yeast
respectively), unwind DNA during transcription (XPB/SsI2 in 3’-5’ direction and XPD/Rad3 in 5’-3’
direction), making TFIIH a bidirectional DNA helicase. The structure of TFIIH has remained the same in
humans and yeast- a complementary study found that a mutation in the SsI2 gene was lethal whereas
mutation in Rad3 gene only led to UV sensitivity, suggesting that only the XPB gene is required for
transcription. However, both of these genes are required for unwinding of DNA during NER.
Transcription consists of the pre-initiation, initiation, promoter clearance, elongation and termination
stages - TFIIH is involved within the pre-initiation stage by binding to the carboxy-terminal repeat
domain (CTD) present on promoter region, creating the pre-initiation complex. CTD is also a kinase
subunit of TFIIH that becomes hyperphosphorylated, which helps the polymerase to be released from the
promoter region and transition from initiation to promoter clearance, establishing the elongation
complex. Furthermore, TFIIH is required for promoter clearance stage, where with TFIIE and ATP, a
region of heteroduplex DNA is created at the start site of transcription, forming a phosphodiester bond.
This suggests that TFIIH and TFIIK are closely associated partners during transcription.
TFIIH is also active during NER, where DNA damage is eradicated from the DNA fragment using the same
DNA helicase encoded by XPB gene - a study that microinjected TFIIH into human XPB/XPD cells led to
repair of damaged DNA, however when using the Rad3 gene, DNA damage was not repaired. This
suggests that NER is active in DNA repair only with TFIIH. However, TFIIK is not necessary for NER as
TFIIH is conjuncted with nucleotide excision repairosome instead. Another function of the TFIIH is the
ability to regulate the cell cycle, by activating cyclin dependent kinases encoded by CDK gene.
Discovery of TFIIH has had major implications for Xeroderma pigmentosum (XP)/XP related diseases,
where the side effects can be explained by transcription defects, rather than deficiencies in DNA repair.
Therefore, this will aid with developing appropriate treatments targeting transcription defects
specifically.
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