Download Rescue of arrested RNA polymerase II complexes

Hypothesis
447
Rescue of arrested RNA polymerase II complexes
Jesper Q. Svejstrup
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK
(e-mail: [email protected])
Journal of Cell Science 116, 447-451 © 2003 The Company of Biologists Ltd
doi:10.1242/jcs.00271
Summary
In the past few months, several discoveries relating to the
mechanism underlying transcription-coupled DNA repair
(TCR) have been reported. These results make it timely to
propose a hypothesis for how eukaryotic cells might deal
with arrested RNA polymerase II (Pol II) complexes. In this
model, the transcription-repair coupling factor Cockayne
Syndrome B (or the yeast equivalent Rad26) uses DNA
translocase activity to remodel the Pol II-DNA interface,
possibly to push the polymerase past the obstruction or to
Introduction
RNA polymerase II will efficiently transcribe DNA only if it
can overcome obstacles on the template strand. Many such
obstacles can be imagined, including DNA-binding proteins,
unusual DNA structures and nucleosomes. However, the most
powerful impediment to the progression of the polymerase is
likely to be DNA lesions (Svejstrup, 2002b). Several types of
DNA lesion are known to block transcription by RNA
polymerase II in vitro as well as in vivo, and, since transcription
is in effect a one-track copying system, an irreversibly trapped
polymerase is unacceptable for the cell, especially if this occurs
in a gene whose continuous productivity is essential for cell
viability. Not surprisingly, therefore, cells have evolved efficient
systems to respond to arrested RNA polymerases (Conaway et
al., 2000; Svejstrup, 2002a).
Hanawalt and colleagues recognized almost two decades ago
that DNA lesions in the transcribed strand of an active gene are
repaired much faster than those in the non-transcribed strand or
in the genome overall (Bohr et al., 1985; Mellon et al., 1986;
Mellon et al., 1987), but, surprisingly, the molecular mechanism
underlying such ‘transcription-coupled’ DNA repair (TCR) is
still unclear. The importance of TCR is evident from the fact
that patients with deficiencies in the repair of lesions in the
transcribed strand of an active gene suffer from a very severe
hereditary disorder, Cockayne syndrome (CS) (de Boer and
Hoeijmakers, 2000). Mutations in genes encoding basal
transcription factors or factors that are required for nucleotide
excision repair (NER) can give rise to both CS and xeroderma
pigmentosum (XP), including those in genes encoding two
subunits of TFIIH (XPB and XPD), and XP group G protein
(XPG). By contrast, mutations in the genes encoding CS group
A (CSA) and CSB (yeast counterpart Rad26) can give rise to
CS but do not result in XP (Balajee and Bohr, 2000; Conaway
and Conaway, 1999; de Boer and Hoeijmakers, 2000). Common
among all these factors is that they have been shown to play a
role in both transcription and DNA repair (Feaver et al., 1993;
Lee et al., 2002b; Lee et al., 2001; Lee et al., 2002c; Schaeffer
et al., 1993; Selby and Sancar, 1997a). Interestingly, the repair
remove it from the DNA so that repair can take place if the
obstacle is a DNA lesion. However, when this action is not
possible and Pol II is left irreversibly trapped on DNA,
the polymerase is instead ubiquitylated and eventually
removed by proteolysis.
Key words: Transcription-coupled repair, Transcript elongation,
Cockayne syndrome, Swi/Snf, Def1, Ubiquitylation, RNA
polymerase II
deficiencies arising as a consequence of these mutations do not
underlie CS, since patients with the repair disorder xeroderma
pigmentosum are unable to repair UV-mediated DNA damage,
both in the transcribed and non-transcribed strand, yet do not
have the same severe clinical features that characterize patients
who suffer (or also suffer) from CS (de Boer and Hoeijmakers,
2000; Lehmann, 2001; Svejstrup, 2002b). Symptoms of CS
such as growth retardation, skeletal and retinal abnormalities
and progressive neural retardation are thus likely to be caused
by transcription deficiencies that may be related to DNA
damage rather than directly to failure to remove DNA damage
from the genome. Very revealing for the possible mechanism of
TCR is the presence of ATPase motifs in the CSB protein. These
motifs are similar to those found in the Snf/Swi-family of ATPdependent chromatin-remodeling enzymes (Eisen et al., 1995).
In this Hypothesis, I discuss the results of four important
recent studies (Lee et al., 2002a; Park et al., 2002; Saha et al.,
2002; Woudstra et al., 2002), which are relevant to the
mechanism of TCR in eukaryotes. On the basis of these
studies, I propose a model for the rescue of arrested Pol II
complexes in which RNA polymerases stalled at DNA lesions
are not considered simply as substrates for a subform of DNA
repair (i.e. TCR) but rather as a problem for transcription that
can be solved in several fundamentally different ways. It is,
however, important to point out that TCR is turning out to be
an extremely complex phenomenon and that the model argued
for here represents only one current interpretation of often
conflicting or at least confusing evidence. For a more
comprehensive review of the literature, the reader is referred
to recent reviews of the field (Balajee and Bohr, 2000;
Conaway and Conaway, 1999; de Boer and Hoeijmakers, 2000;
Svejstrup, 2002b).
A stalled polymerase triggers a rapid cellular
response
The idea that damage-stalled Pol II is an unacceptable
occurrence in cells stems from the fact that DNA damage in
448
Journal of Cell Science 116 (3)
the transcribed strand of an active gene is preferentially
repaired even though – in theory – the stalled polymerase
covers the lesion and therefore should make it less accessible
to the repair machinery. Several lines of evidence support the
suggestion that Pol II itself triggers rapid repair. First,
preferential repair of the transcribed strand of an active gene
ceases immediately if Pol II transcription is stopped by the use
of drugs (α-amanitin) or elevated temperature (in yeast strains
expressing temperature-sensitive versions of Pol II) (Christians
and Hanawalt, 1992; Sweder and Hanawalt, 1992). Further
persuasive evidence comes from work on the rates of repair in
and around active genes, mostly in yeast (Teng and Waters,
2000; Tijsterman and Brouwer, 1999; Tijsterman et al., 1999;
Tijsterman et al., 1996; Tijsterman et al., 1997; Tu et al., 1997;
Tu et al., 1998; Tu et al., 1996). TCR is generally observed
only in the open reading frame of an active gene but not in the
promoter or in the region downstream from the transcription
termination sites. It has also been shown that the rate of repair
in the non-transcribed strand, but not in the transcribed strand,
is significantly affected by the presence of nucleosomes
(Tijsterman et al., 1999; Wellinger and Thoma, 1997).
Importantly, repair on the non-transcribed strand is much
slower at the cores of positioned nucleosomes than in
internucleosomal regions, whereas the rate of repair on the
transcribed strand is largely independent of the presence and
position of the same nucleosomes. However, certain lesions in
the internucleosomal regions are repaired more slowly in the
transcribed strand than in the non-transcribed strand if TCR is
perturbed by deletion of RAD26, which encodes the yeast
homologue of CSB. The simplest interpretation of these results
is that NER at what are likely to be more accessible sites is
actually obstructed by Pol II in the transcribed strand and that
one function of Rad26 (and, by extension, CSB) is somehow
to remove the polymerase so that repair can take place
(Tijsterman et al., 1999).
The Swi/Snf-like ATPase activity of CSB/Rad26 and
its role in removal of Pol II from DNA damage
So how might CSB/Rad26 help remove Pol II? Several
possibilities should be considered. First, it might remodel the
Pol-II–DNA interface to make the lesion more accessible.
Second, it might release Pol II from the site of DNA damage.
Third, it might promote damage bypass by Pol II. As
mentioned above, CSB/Rad26 is an ATPase in the Swi/Snffamily (Eisen et al., 1995) and has a prokaryotic counterpart,
transcription repair coupling factor (TRCF) (Park et al., 2002;
Selby and Sancar, 1993). Significantly, in a compelling recent
study of TRCF, Park et al. discovered that this protein is an
ATP-dependent DNA translocase that can move RNAP
forward on DNA (Park et al., 2002). Thus, TCRF can ‘push’ a
stalled polymerase whose active site is out of register with the
end of the RNA up to the end of the nascent RNA so that it
can continue transcription if nucleotides and a clear (DNA)
path are present. A well established feature of TRCF is its
ability to displace RNAP from DNA when nucleotides are
absent or if an obstacle is in the way. So, bacterial TRCF is
also capable of pushing RNAP off the DNA if the arrest is due
to a DNA lesion (Selby and Sancar, 1993). This feature does
not seem to be conserved in the eukaryotic counterpart, CSB,
which is unable to displace Pol II from a damage site (Selby
and Sancar, 1997b). Since CSB and Rad26 are only distantly
related to TRCF (except for limited homology in the ATPase
domains) (Eisen et al., 1995), it would thus have been
reasonable for researchers interested in eukaryotic CSB/Rad26
not to pay too much attention to the lessons learnt from
bacterial TRCF. However, two pieces of evidence should be
mentioned that are important for building working models of
the mechanism used by the eukaryotic factors. First, CSB can
promote the addition of an extra nucleotide by Pol II stalled at
a DNA lesion (Selby and Sancar, 1997a). Second, a recent
study on the reaction mechanism of eukaryotic Swi/Snf-like
enzymes reports that the Swi/Snf-like enzyme RSC, like
TCRF, is a DNA translocase (Saha et al., 2002). The data from
Cairns and co-workers raise the possibility that all Swi/Snf-like
enzymes move proteins about on DNA by pulling or pushing
the DNA. For Swi/Snf-like enzymes, such as RSC, CHRAC,
ISWI and Swi/Snf itself (Cairns, 1998; Langst and Becker,
2001), the target protein is likely to be nucleosomes, but in the
case of family members such as Rad54, Rad16 and CSB/Rad26
(Eisen et al., 1995), the target could be something else,
although nucleosomes might also be moved, as has been
demonstrated in vitro (Citterio et al., 2000). In the case of
CSB/Rad26, a primary target could be Pol II. As already
mentioned, the action of CSB/Rad26 could in theory allow the
Pol-II–DNA interface to be remodeled so that repair can take
place. Alternatively/additionally, it could sometimes allow Pol
II to be pushed past the site of DNA damage or perhaps to be
displaced, all depending on the lesion and the context in which
it is found. The possibility that accessory factors are required
for some of these events is also important in this connection.
The data so far obtained on the mechanism of CSB/Rad26
action have thus been derived by the use of purified
recombinant proteins (Citterio et al., 2000; Guzder et al., 1996;
Selby and Sancar, 1997a; Selby and Sancar, 1997b), rather than
the native protein, which might well exist in a complex (van
Gool et al., 1997; Woudstra et al., 2002).
Proteolysis of Pol II in response to DNA damage
But what happens if the action of CSB/Rad26 on damagestalled Pol II does not solve the problem? In light of the
considerations mentioned above, this might require much more
drastic action. Important in this connection, Pol II becomes
ubiquitylated and degraded in response to DNA damage
(Beaudenon et al., 1999; Bregman et al., 1996; Luo et al., 2001;
Ratner et al., 1998), which raises the possibility that it is
removed from lesion sites so that rapid repair can take place.
However, enabling TCR is unlikely to be the function of Pol II
proteolysis (Lommel et al., 2000; Woudstra et al., 2002).
Rather, a new study suggests that ubiquitylation and Pol II
degradation in response to DNA damage constitutes an
alternative to DNA repair – a last resort (Woudstra et al., 2002).
Woudstra et al. purified yeast Rad26 from soluble (DNAfree) as well as salt-stable chromatin and found that it exists in
different forms. The form isolated from the soluble fraction
does not appear to be associated with any other protein,
whereas the form extracted and purified from chromatin is
associated with a novel protein, Def1. Cells lacking DEF1 have
phenotypes that indicate that this protein has a role in the DNA
damage response as well as in Pol II transcript elongation.
Remarkably, def1∆ cells are not UV sensitive and perform
Rescue of arrested RNA polymerase II complexes
449
TCR efficiently. However, when def1∆ is combined with
mutations that reduce or abolish the ability of cells to repair
DNA damage, cells become extremely sensitive to UV
damage, which suggests that Def1 participates in a pathway
that represents an alternative to DNA repair. This pathway
turns out to be the ubiquitylation-mediated proteolysis
pathway, and the target is Pol II. Thus, cells lacking DEF1 are
unable to ubiquitylate and degrade Pol II in response to UV
damage. Interestingly, cells lacking RAD26 behave in the
opposite way: here, Pol II is very rapidly and much more
completely destroyed in response to damage than is the case in
wild-type cells. However, in cells lacking both DEF1 and
RAD26, Pol II degradation is somewhat restored. Rad26 and
Def1 might thus functionally interact in vivo to regulate the
degradation of Pol II in response to DNA damage (Woudstra
et al., 2002). Interestingly, work in mammalian cells has shown
that ubiquitylation and Pol II degradation are impaired, not
increased, in the absence of functional CSB (Bregman et al.,
1996; Luo et al., 2001; McKay et al., 2001). At first glance,
the function of yeast Rad26 and human CSB thus appears to
differ fundamentally. However, a possible explanation for the
difference could be that the function of both CSB and the
presumed Def1 homologue is compromised by mutation of
CSB in man, whereas Rad26 and Def1 are able to perform their
functions independently in yeast. In support of this scenario,
gel filtration experiments have shown that (in contrast to yeast
Rad26), human CSB normally exists in a large protein complex
(van Gool et al., 1997). The function of this entire complex
(including Pol II degradation) might thus be compromised by
CSB mutation.
An important recent study by Sharp and colleagues supports
the idea that arrested Pol II is a target of ubiquitylation (Lee et
al., 2002a). Here, it was shown that ubiquitylation of Pol II
during transcription in vitro is significantly induced by αamanitin, which blocks Pol II transcript elongation and
also causes Pol II degradation inside cells (Nguyen et
al., 1996). In agreement with the above interpretation
'Normal' arrest/stall
Damage arrest/stall
of the data from Woudstra et al. (Woudstra et al., 2002),
Pol II
Pol II undergoes similar ubiquitylation on DNA
containing cisplatin adducts (DNA lesions) that arrest
transcription (Lee et al., 2002a). Together, the data by
A lesion
RNA
NA
Woudstra et al. and Lee et al. thus suggest that Pol II
General elongation
is subject to ubiquitylation whenever it arrests during
factors (TFIIS, etc.)
transcription and that this can lead to its degradation
(Lee et al., 2002a; Woudstra et al., 2002).
Continued
transcription
Many arrested/stalled
complexes rescued
No rescue
CSB/Rad26 action
Continued
transcription
More arrested/stalled
complexes rescued
Some lesion-arrested
complexes rescued by
damage bypass
Some lesion-arrested
complexes rescued by
remodeling and TCR
A model for repair of damage-stalled Pol II
elongation complexes
The data described above make it possible to propose
a hypothesis for the events that occur when Pol II
arrests during transcription, and particularly in
response to transcription-impeding DNA
lesions in genes (Fig. 1). Most arrests can
probably be resolved by the actions of
Continued
general elongation factors (Conaway et al.,
transcription
2000; Svejstrup, 2002a). However, Pol II
will also arrest at DNA lesions; so
transcription of the gene becomes blocked.
General elongation factors are unlikely to be
of much help under such circumstances, and
the action of, for example, Spt4/5 might
Continued
transcription
Def1, ubiquitination
ub
ub
ub
ub
ub
Continued
transcription
ub
Some arrested complexes rescued by 19S-dependent
manipulation of the structure of the Pol-II–DNA complex
Pol II proteolysis
Pol II transcribes
the gene
Continued
transcription
DNA lesion removed
by other repair mechanisms
Fig. 1. Hypothesis for a step-wise mechanism to
resolve arrested Pol II elongation complexes.
Two examples of arrested Pol II complexes and
how they might be resolved are shown. On the
right is an elongation complex arrested at a DNA
lesion, and on the left is a complex arrested for
other reasons. General elongation factors such as
TFIIS play an important role for the resolution
of the latter complex but have little effect on
damage-stalled Pol II. By contrast, CSB/Rad26
can affect the resolution of both types of
complexes. If such resolution fails, ubiquitin(and Def1-) related mechanism come into play.
This does not necessarily always involve Pol II
proteolysis, which might only be the final
solution to the problem.
450
Journal of Cell Science 116 (3)
actually be counter productive (Jansen et al., 2000). However,
in the model, arrested Pol II also leads to recruitment of
Rad26/CSB and Def1. Rad26 might have two major effects.
First, it might inhibit Pol II degradation, leaving time for the
stalled complex to be dealt with through other mechanisms
(Woudstra et al., 2002). Second, the catalytic activity of
CSB/Rad26 itself (perhaps its DNA translocase activity) could
‘remodel’ the Pol-II–DNA interface (and possibly
nucleosomes as well), and its reported interactions with TFIIH
might facilitate the recruitment of repair proteins when the stall
is due to DNA damage (Tantin, 1998; Tantin et al., 1997). The
Pol-II–DNA remodeling might involve translocation of the
DNA in the direction of the polymerase [as RSC does with
nucleosomes (Saha et al., 2002)], so that the lesion bulges out
and can be readily repaired. Alternatively, the protein might
translocate DNA in the direction away from the polymerase [as
bacterial TRCF does with RNA polymerase (Park et al., 2002)]
so that the polymerase is forced forward to the end of the RNA
and perhaps to the other side of a lesion (where it can continue
transcription, perhaps skipping or mis-incorporating a base) or
is displaced off the DNA.
According to the model, if arrested Pol II complexes cannot
be resolved by general elongation factors or CSB/Rad26related mechanisms, Pol II is now ubiquitylated in a process
that is at least partially dependent on Def1. Whether there is
damage or not, this clears the path for alternative pathways of
resolution. Because both repair and transcript elongation is
affected by proteolysis-independent functions of the 19S
regulatory complex of the proteasome (Ferdous et al., 2001;
Gillette et al., 2001; Russell et al., 1999), it is possible that
ubiquitylation does not always result in Pol II degradation.
Johnston and co-workers have thus proposed that the 19S
complex might somehow manipulate the structure of the Pol II
elongation complex by proteolysis-independent mechanisms to
facilitate transcription (Ferdous et al., 2001). However, when
all else fails, ubiquitylation of Pol II would eventually lead to
its degradation by the proteasome, allowing transcription of the
gene to be completed by the subsequent polymerase and repair
to take place by transcription-independent pathways.
It is important to remember that the action of CSB/Rad26
and ubiquitylation factors such as Def1 is not confined to
situations in which there is DNA damage. These proteins are
likely to have similar roles when cells try to rescue Pol II
elongation complexes that are stalled for reasons other than
DNA damage (such as DNA structure or sequence context,
protein blocks, etc.). In support of this idea, CSB affects
transcript elongation of undamaged DNA in vitro (Selby and
Sancar, 1997a), and cells lacking RAD26 have transcription
defects in vivo (Lee et al., 2001). def1∆ cells also have defects
consistent with a role for this protein in transcript elongation
in the absence of DNA damage (Woudstra et al., 2002). The
possibility that cells make overall transcription more efficient
by clearing Pol II ‘roadblocks’ through proteolysis of the
polymerase in the absence of DNA damage clearly deserves
further attention.
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