2.2. Introduction of TFIIH
TFIIH is a multifunctional 10-subunit protein complex integral to both
NER and transcription. The TFIIH complex includes a 7-subunit core,
which consists of XPB, XPD, p52, p8, p62, p34, and p44, and a
three-subunit cyclin activated kinase (CAK) module, which consists of
CDK7, cyclin H, and MAT1 (Tsutakawa et al., 2020) (Figure 1 ).
During transcription, TFIIH is part of the preinitiation complex (PIC)
and functions for promoter opening and RNA Pol II phosphorylation. The
XPB subunit in TFIIH, an ATP-dependent DNA translocase, is particularly
important for opening promoter DNA (Dienemann et al., 2019; Fishburn et
al., 2015). The CAK kinase module in TFIIH phosphorylates Ser5 in RNA
Pol II C-terminal domain to stimulate promoter escape of Pol II from the
initiator element (Helenius et al., 2011; Wong et al., 2014).
However, when damage is recognized by NER surveillance proteins, UV-DDB
and XPC, or the stalling of RNA Pol II, TFIIH is reallocated to damage
for the NER pathway and there will be a decrease in TFIIH
transcriptional activity until the damage is repaired (Coin et al.,
2008). Different from its role in transcription, TFIIH mainly performs
the helicase function to keep open the DNA bubble, and facilitate
recruitment of downstream repair proteins. The helicase function is
solely dependent on the 7-subunit core complex, but does not require the
CAK kinase module. Interestingly, it has been shown that CAK needs to be
displaced from TFIIH by XPA, and the displacement activates the repair
function of TFIIH (Coin et al., 2008). CAK has been shown to negatively
regulate the helicase activity of XPD and also phosphorylate one or more
TFIIH and NER components (Araújo et al., 2000). Therefore, dissociation
of the CAK complex from the TFIIH core can stimulate the helicase and
ATPase activities of other subunits, allowing for the DNA strand to be
opened and enlarged around the site of damage (Winkler et al., 2001). On
the other hand, the p44 subunit interacts with XPD and can enhance XPD’s
ATPase activity in vitro (Dubaele et al., 2003).