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J Biol Chem, Vol. 273, Issue 9, 5184-5189, February 27, 1998
From the We have shown previously that UV radiation and
other DNA-damaging agents induce the ubiquitination of a portion of the
RNA polymerase II large subunit (Pol II LS). In the present study UV
irradiation of repair-competent fibroblasts induced a transient reduction of the Pol II LS level; new protein synthesis restored Pol II
LS to the base-line level within 16-24 h. In repair-deficient xeroderma pigmentosum cells, UV radiation-induced ubiquitination of Pol
II LS was followed by a sustained reduction of Pol II LS level. In both
normal and xeroderma pigmentosum cells, the ubiquitinated Pol II LS had
a hyperphosphorylated COOH-terminal domain (CTD), which is
characteristic of elongating Pol II. The portion of Pol II LS whose
steady-state level diminished most quickly had a relatively hypophosphorylated CTD. The ubiquitinated residues did not map to the
CTD. Importantly, UV-induced reduction of Pol II LS level in
repair-competent or -deficient cells was inhibited by the proteasome inhibitors lactacystin or MG132. These data demonstrate that UV-induced ubiquitination of Pol II LS is followed by its degradation in the
proteasome. These results suggest, contrary to a current model of
transcription-coupled DNA repair, that elongating Pol II complexes which arrest at intragenic DNA lesions may be aborted rather than resuming elongation after repair takes place.
Ubiquitination of cellular proteins is a covalent modification
that plays several important physiological roles (1, 2). Proteins
become ubiquitinated by the sequential action of three enzymes: a
ubiquitin-activating enzyme
(E1),1 a
ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3).
Because ubiquitinated proteins are usually targeted for
degradation in the proteasome, this modification enables cells to
control the level of many regulatory proteins (1-3). Some ubiquitinated proteins, however, are not targeted to the proteasome (4-6).
Ubiquitination plays a role in the response of the cell to DNA damage
including the accumulation of p53 (7, 8). Mammalian cells with a
temperature-sensitive E1 show increased sensitivity to ultraviolet (UV)
radiation when grown at the non-permissive temperature (9). The yeast
RAD6 gene encodes an E2 (10), and the product of the yeast
RAD23 gene possesses an NH2-terminal ubiquitin-like domain that is essential for its role in DNA repair (11). Lastly, a proteasomal subunit (SUG 1) copurifies with TFIIH, a multiprotein complex required for transcriptional initiation by RNA polymerase II (Pol II) as well as DNA repair via the nucleotide excision repair (NER) pathway (12, 13).
7-10% of the large subunit of RNA polymerase II (Pol II LS) becomes
ubiquitinated within minutes of exposing cultured human cells to UV
radiation and the anti-cancer agent cisplatin (14). These two agents
cause DNA lesions subject to repair by NER (7). Lesions induced by UV
radiation and cisplatin can stop transcription by creating a physical
block for the elongating Pol II apparatus when the lesions are located
on the transcribed strand of a gene. Such lesions are repaired more
rapidly by the NER pathway than are lesions located elsewhere in the
genome. This preferential repair, called transcription-coupled repair
(TCR), requires a functional Pol II LS (for review, see Ref. 13). Cells
from patients with Cockayne syndrome (CS) demonstrate deficient TCR and
hampered recovery of transcriptional activity after UV irradiation
(15). Two complementation groups (CS-A and CS-B) have been identified, and in both cases the defective gene has been cloned (16, 17). Interestingly, CS-A and CS-B cells also demonstrate deficient UV-induced ubiquitination of Pol II LS (14). A portion of Pol II binds
to the CS-B protein (18).
During the transcription cycle, the COOH-terminal domain (CTD) of Pol
II LS undergoes a cycle of phosphorylation/dephosphorylation (19, 20).
A relatively hypophosphorylated form of Pol II LS (IIa) preferentially
binds to most promoters. Promoter clearance and transcript elongation
are associated with phosphorylation of the CTD to yield a
hyperphosphorylated (IIo) form. The CTD is an essential component of
Pol II LS. It is comprised of a heptapeptide with the consensus
sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser repeated 52 times in mammalian
cells. Many proteins involved in transcriptional regulation (21, 22) as
well as pre-mRNA processing (23-25) bind to the CTD, and it
appears likely that the phosphorylation status of the CTD helps
determine which proteins will bind (26). Studies of CTD phosphorylation
have been assisted by the characterization of monoclonal antibodies
(mAbs) that recognize distinct epitopes within the repeated
heptapeptide (27, 28). Some mAbs recognize a phosphorylated Ser residue
(H5 or H14) and others recognize a dephosphorylated Ser residue (8WG16)
within the repeated
heptapeptide.2
Because the status of Pol II LS after the cell has sustained DNA damage
may affect NER as well as the recovery of transcription, we wished to
determine the metabolic fate of Pol II LS subsequent to UV-induced
ubiquitination. In the present study we establish that UV-induced
ubiquitination of a portion of Pol II LS is followed by transient
diminution of its steady-state level. Whereas the ubiquitinated Pol II
LS molecules have a hyperphosphorylated CTD, the portion that appears
to diminish most rapidly has a hypophosphorylated CTD. In
repair-competent fibroblasts, new protein synthesis permits recovery of
base-line Pol II LS level. In repair-deficient xeroderma pigmentosum
(XP) cells, the loss of Pol II LS is sustained. Proteasome inhibitors
block the loss of Pol II LS in repair-competent or -deficient cells.
The ubiquitinated residues are not located in the CTD.
Cell Culture--
Cell culture was performed as described
previously (14). The following XP fibroblast lines were used: DNA
repair-competent, GM5659C and GM639D; XP-A, GM2009; XP-C, GM671; XP-D,
GM8207; and XP-G, GM3021 from the National Institute of General Medical
Sciences Human Genetic Mutant Cell Repository (Camden, NJ). They were
maintained in Eagle's minimal essential medium (Sigma) supplemented
with 15% fetal bovine serum, 2 mM L-glutamine,
and 1 × penicillin-streptomycin-neomycin (Sigma). UV irradiation
at 254 nm was performed as described previously (14).
Ultraviolet Radiation-induced Ubiquitination and Proteasomal
Degradation of the Large Subunit of RNA Polymerase II
IMPLICATIONS FOR TRANSCRIPTION-COUPLED DNA REPAIR*
,,
Department of Pathology, Albert Einstein
College of Medicine, Bronx, New York 10461, the
§ Department of Molecular Biology and Genetics, The Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205, and
¶ NeXstar Pharmaceuticals, Boulder, Colorado 80301
ABSTRACT
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Abstract
Introduction
Procedures
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Procedures
Results
Discussion
References
EXPERIMENTAL PROCEDURES
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Introduction
Procedures
Results
Discussion
References
Pol II LS Immunoblot Analysis-- 6% SDS-PAGE and Western immunoblot analysis of whole cell extracts of cultured cells were performed as described previously (14) with the following mAbs directed against Pol II LS: H5 and H14 (27), ARNA 3 (Research Diagnostics, Flanders, NJ), and 8WG16 (QED Biosciences, San Diego, CA). Protein bands were visualized via chemiluminescence (Pierce) after blotting with peroxidase-conjugated goat anti-mouse IgM for H5 (diluted 1:10,000) and H14 (diluted 1:20,000) or horseradish peroxidase-conjugated goat anti-mouse IgG for 8WG16 and ARNA 3 (diluted 1:10,000).
The cell fractionation experiment was performed by extracting fibroblasts with TD buffer (0.5% Triton X-100, 0.5% sodium deoxycholate, 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM phenylmethylsulfonyl fluoride) as described previously (27). Insoluble material was solubilized with SDS-PAGE sample buffer, and equicellular amounts of TD extractable and unextractable material were subjected to immunoblot analysis.Mapping Pol II LS Ubiquitination Sites to a Non-CTD
Domain--
HeLa cells were stably transfected with two different
constructs expressing 
-amanitin-resistant Pol II LS: pHA-Wt, which expresses a hemagglutinin (HA)-tagged, -amanitin resistant,
full-length murine Pol II LS; and pHA-D31, which is identical to pHA-Wt
except that the CTD has only 31 heptapeptide repeats such that all 8 CTD lysine residues are removed. The HeLa cells were transfected via
lipofection with LipofectAMINE (Life Technologies, Inc.), and then
cells expressing the -amanitin-resistant Pol II LS were selected
with 2 mg/ml -amanitin. Clones of cells expressing pHA-Wt or pHA-D31
were then UV irradiated, allowed to recover at 37 °C, and were
subjected to lysis in hot 1% SDS, 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM phenylmethylsulfonyl
fluoride. Lysates were incubated in a boiling water bath for 5 min and
then diluted with 6 volumes of cold 0.5% Triton X-100, 0.5% sodium
deoxycholate, 50 mM Tris-HCl, pH 7.5, 150 mM
NaCl, 1 mM phenylmethylsulfonyl fluoride and placed in on
ice. Immunoprecipitation was performed as described previously (14)
with anti-HA mAb 12CA5 (Babco, Richmond, CA) non-covalently coupled to
protein G-Sepharose beads (Pharmacia Biotech Inc.). Immunoprecipitated
material was then subjected to immunoblot analysis with mAb H14.
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RESULTS |
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Discussion
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UV Radiation Temporarily Reduces Pol II LS Level in Repair-competent Cells-- Because ubiquitinated proteins are often targeted to the proteasome, we investigated whether UV-induced ubiquitination of Pol II LS was followed by its degradation. Repair-competent fibroblasts were subjected to UV irradiation and allowed to recover at 37 °C for 1-24 h. Whole cell extracts from equivalent numbers of cells were prepared and subjected to Western immunoblot analysis with H14, a mAb that binds specifically to Pol II LS (Fig. 1A, lanes 1-6). The H14 immunoreactive band from unirradiated cells is characteristically broad because H14 recognizes the hyperphosphorylated (IIo), hypophosphorylated (IIa), and intermediate forms of Pol II LS (Fig. 1A, lane 1). 1 h after a dose of UV radiation which would be expected to kill 10-25% of repair-competent fibroblasts (29, 30), ubiquitinated forms of Pol II LS could be identified (Fig. 1A, lane 2). These forms migrate more slowly than IIo and have been demonstrated previously to represent ubiquitinated Pol II LS (14). In addition, the samples isolated 1-8 h after UV irradiation have a less broad Pol II LS band in which the relatively hypophosphorylated (IIa) forms appear preferentially diminished (lanes 2-4). By 16-24 h after UV irradiation, the band width and intensity more closely resemble the unirradiated sample (lanes 5 and 6). This loss of Pol II LS was not appreciated in earlier studies (14) most likely because sublethally irradiated HeLa cells divide and resynthesize Pol II LS very rapidly. Similar results were obtained when cell extracts were normalized for total protein content (data not shown).
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UV Radiation Induces a Sustained Reduction of Pol II LS Level in XP-D Cells-- We also performed a UV time course in an NER-defective xeroderma pigmentosum group D (XP-D) fibroblast cell line. In Fig. 1, A and B, it can be seen that ubiquitination and deubiquitination occur with similar kinetics in the repair-competent and XP-D cells. However, in the XP-D cell line the UV-induced diminution of the hypophosphorylated forms of Pol II LS is sustained. The broad Pol II LS band seen in the unirradiated base line is not restored by 16-24 h as it is in the repair-competent cells (compare Fig. 1A, lane 12 with lane 6, or Fig. 1B, lane 24 with lane 18). The fact that the diminution of Pol II LS from XP-D cells can be demonstrated in the immunoblots performed with H14, ARNA 3, and 8WG16 provides further proof that UV induces a net loss of protein rather than a change in CTD phosphorylation. Furthermore, the XP-D data demonstrate the preferential binding of mAb H5 to the IIo form of Pol II LS and its ability to recognize the ubiquitinated forms of Pol II LS (compare Fig. 1A, lanes 19 and 20 with lanes 7 and 8).
Reduction of Pol II LS Level Is the Result of Proteasomal Degradation-- If the UV-induced down-regulation of the Pol II LS steady-state level was caused by protein degradation, recovery of Pol II LS to the base-line level in repair-competent cells should require new protein synthesis. A UV time course performed in the presence of the protein synthesis inhibitor cycloheximide demonstrated that this is indeed the case (Fig. 2).
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, lanes 6 and
12).
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Characterization of the Ubiquitinated Fraction of Pol II LS-- The ubiquitinated portion of Pol II LS was shown to be hyperphosphorylated (IIo) by virtue of its immunoreactivity with mAb H5 (Fig. 1A). Whereas many studies have shown that Pol II LS that is actively engaged in transcriptional elongation is in the IIo form, we have shown previously that a portion of IIo is also present in a transcriptionally quiescent extrachromosomal location where splicing factors are also located (23, 27). These two different pools of IIo differ substantially in their ability to be extracted from mammalian nuclei with non-ionic detergents (27). The non-chromosomal (transcriptionally inactive) form is considerably more resistant to detergent extraction than the non-speckle-associated form. We demonstrated that the ubiquitinated form of Pol II LS is readily extractable with non-ionic detergent (Fig. 4). None of the ubiquitinated IIo was detected in the detergent-inextractable fraction, even when long exposures of the immunoblot were examined (data not shown). This is consistent with ubiquitinated IIo being the transcriptionally active (elongating) form of Pol II LS.
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Mapping the Sites of Ubiquitination to a Non-CTD Domain-- Because the ability of Pol II LS to be ubiquitinated appears to depend on the phosphorylation status of the CTD, we wished to determine whether ubiquitination was also localized to this important regulatory domain. The CTD of Pol II LS is comprised of 52 tandem repeats of a heptapeptide with the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. All covalent modifications of Pol II LS besides ubiquitination, including serine/threonine phosphorylation, tyrosine phosphorylation, and O-linked glycosylation, have been mapped to the CTD (34-36). We therefore wished to determine whether ubiquitination maps to this domain of Pol II LS.
We were able to replace functionally the Pol II LS of HeLa cells with a truncated molecule in which all potential ubiquitination sites within the CTD were removed. Ubiquitination occurs exclusively on lysine residues (1). The CTD includes 8 lysines all of which are located in the COOH-terminal third of the CTD (comprising heptapeptide repeats 34-52) (37). Truncation of more than half of the CTD prevents its normal function, but truncation of the portion of the CTD including all 8 lysine residues yields a molecule capable of supporting a viable cell (38). Furthermore, a mutated variant of mouse Pol II LS has been cloned which will render cells resistant to the transcriptional inhibitor-amanitin. This mutant bears a single amino acid change at a non-CTD
amino acid (39). In a cell expressing both WT (human) Pol II LS and
mutant (mouse) Pol II LS, only the mutant will function in the presence
of -amanitin (40). The amino acid sequences of WT mouse and human
Pol II LS are nearly identical; there are only two sequence
differences, neither of which involves CTD lysine residues (37).
We therefore isolated HeLa cells stably transfected with
-amanitin-resistant Pol II LS expression constructs bearing either full-length CTD with all 52 heptapeptide repeats (WT) or a truncated CTD with only 31 of 52 heptapeptide repeats which therefore lacked all
8 CTD lysine residues (
31). These constructs were HA epitope tagged
so the product of the transfected construct could be separated from the
host Pol II LS via specific immunoprecipitation. After UV irradiation,
both WT and truncated HA-tagged Pol II LS molecules demonstrated
ubiquitination thus proving that non-CTD lysine residues were being
ubiquitinated (Fig. 5).
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UV-induced Ubiquitination of Pol II LS in XP Cells-- To address the question of whether UV-induced ubiquitination of Pol II LS plays a mechanistic role in NER, we investigated Pol II LS ubiquitination in fibroblast cell lines established from patients with XP complementation groups A through G. Each complementation group lacks a functional gene product required for a mechanistic "step" of NER (7). In addition several forms yield defects in TCR (XP-B, -D, and -G) (13). If ubiquitination of Pol II LS plays a mechanistic role in NER or TCR, ubiquitinated Pol II LS might accumulate to unusually high levels in one or more of the XP subtypes, or the kinetics of the appearance/disappearance of ubiquitinated Pol II LS might be altered.
In Fig. 6A, UV time courses of two different repair-competent human fibroblast lines are shown (lanes 1-5 and 6-10). Ubiquitinated forms of Pol II LS are induced within 1 h after UV irradiation and diminish thereafter until they become undetectable by 16-24 h. In all XP cells, ubiquitination and deubiquitination occurred to an extent similar to that seen in repair-competent cells and with similar kinetics (lanes 11-25). The results of XP-B, -D, -E, and -F cells (data not shown) were the same as those shown for XP-A and -G cells. These results do not support a mechanistic role for ubiquitination of Pol II LS in NER.
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This study establishes that UV radiation induces ubiquitination of a fraction of Pol II LS which is followed by the degradation of a fraction of Pol II LS in the proteasome. Another recent study identified a specific ubiquitin-protein ligase (Rsp5) capable of ubiquitinating Pol II LS in vitro and in vivo (43). The ability to inhibit the UV-induced reduction of Pol II LS steady-state level with MG132 or lactacystin, two proteasomal inhibitors, supports the conclusion that degradation takes place in the proteasome (Fig. 3).
Thus DNA repair-competent cells appear capable of temporarily
down-regulating their Pol II LS level upon transcriptional arrest and
then reaccumulating new Pol II LS when transcription resumes (Figs. 1
and 6). In repair-deficient cells or in those repair-competent cells
subjected to a lethal (50 J/m2) UV dose, Pol II LS levels
remain low (Fig. 6). In XP-C cells, which maintain the ability to
repair DNA damage and therefore recover transcriptional activity
through TCR (they are only deficient in genome overall repair), Pol II
LS levels also return to the base-line level within 16-24 h (Fig. 6).
Evidence for post-transcriptional regulation of the Pol II LS level
already exists in Caenorhabditis elegans (44). In mammalian
cells, -amanitin and actinomycin D can also trigger Pol II LS
degradation (45). Pol II LS is a component of the nuclear matrix, and
its degradation may render DNA more susceptible to fragmentation of the
sort observed during apoptosis (46).
The results of this study are complicated by the fact that multiple phosphorylated forms of Pol II LS exist. Although the form that gets ubiquitinated is highly phosphorylated, the forms whose steady-state level decreases most rapidly are less phosphorylated (e.g. see Fig. 1A). Because mAb H5, which is specific for highly phosphorylated Pol II LS (27), reacts with the ubiquitinated forms of Pol II LS (Fig. 1A, lanes 14-17 and 20-23) it can be concluded that the ubiquitinated form of Pol II LS is also highly phosphorylated. Furthermore, an antibody that recognizes a non-phosphorylated CTD epitope (mAb 8WG16) does not react with the ubiquitinated forms (Fig. 1B, lanes 14-17 and 20-23). It should be noted that both H14 and 8WG16 recognize overlapping broad Pol II LS bands because the CTD of one Pol II LS molecule may have phosphorylated as well as non-phosphorylated heptapeptides. Presumably, the number and identity of phosphorylated versus non-phosphorylated residues among the approximately 250 serines, threonines, and tyrosines within the CTD determine the migration rate in SDS-PAGE.
A plausible interpretation of these steady-state results is that UV-induced ubiquitination and subsequent degradation of Pol IIo prevent its being recycled (via dephosphorylation) to the IIa form so that the steady-state level of IIa diminishes. The pool of IIa gets converted to IIo via the action of one or more CTD kinases. Some CTD kinases phosphorylate IIa to IIo during the normal transcription cycle, and others may be activated by heat shock or other cellular stresses (47, 48). In the present study, some reduction in the level of Pol IIo did become apparent when resynthesis of Pol II LS was prevented with cycloheximide (Fig. 2) or when XP-D cells were irradiated so that transcription could not resume (see Fig. 1A).
Although the present study does not demonstrate directly that the fraction of Pol II LS which gets ubiquitinated and degraded is stalled at intragenic lesions, the results are consistent with this conclusion. It is known that UV-induced DNA lesions constitute a potent block to transcription at which elongating Pol II becomes stably arrested (49). The large subunit of arrested Pol II would be expected to exist in the IIo form. Western immunoblot analysis demonstrated that ubiquitinated Pol II LS reacts with mAb H5, which is specific for the IIo form. Although a previous study demonstrated a transcriptionally quiescent fraction of H5-immunoreactive Pol II LS present in structures called speckles or interchromatin granule clusters (27), we utilized the extractability of non-speckle-associated IIo with non-ionic detergent to strengthen the argument that the ubiquitinated IIo is not present in the speckles (Fig. 6). Furthermore, we have shown previously that UV-induced ubiquitination of Pol II LS is deficient in CS-A and CS-B fibroblasts, which have a defect in TCR. Thus it seems quite likely that elongating Pol II LS that arrests at intragenic DNA lesions becomes ubiquitinated and gets degraded in the proteasome. Future studies will be aimed at demonstrating directly that the stalled Pol II molecules get ubiquitinated.
The results presented here also establish that ubiquitination occurs on non-CTD lysine residues (Fig. 5). It will be of interest to determine whether the ubiquitinated lysine residues are located within DNA binding domains and whether ubiquitination per se promotes dissociation of the stalled Pol II from the DNA before Pol II LS degradation in the proteasome.
A current model of TCR in eukaryotes suggests that arrested transcripts back up, possibly assisted by elongation factor SII, then resume elongating after the lesion has been repaired (50, 51). This model is supported by the stability of DNA·Pol II·pre-mRNA ternary complexes arrested at intragenic lesions in in vitro DNA damage systems as well as by the belief that it would be metabolically wasteful for cells to abort partially elongated RNA transcripts. An important implication of the results presented in this study is that an elongating Pol II complex that arrests at an intragenic lesion will not finish elongating the interrupted transcript after repair takes place. If Pol II LS is ubiquitinated and degraded in the proteasome it suggests that the arrested transcript is aborted. Thus eukaryotic Pol II LS may behave as Escherichia coli RNA polymerase behaves. In E. coli the product of the mfd gene, TRCF, releases the arrested DNA·RNA polymerase·RNA ternary complex and recruits the bacterial NER apparatus (the UvrA2UvrB1 complex) to the intragenic lesion (52).
Two lines of evidence (in addition to the results presented in this study) support the idea that SII, although essential for allowing Pol II to negotiate intrinsic pause sites, may be less important for TCR and/or the ability of cellular transcription levels to resume base-line levels after being arrested by UV-induced DNA damage. First, yeast with mutated SII does not demonstrate a deficiency in TCR (53), suggesting that SII is not essential for either the preferential repair of intragenic DNA lesions or the ability of transcription to resume once such lesions have been repaired. Second, a recent in vitro study leads to the conclusion that SII may be more effective at allowing Pol II to bypass lesions that cause the slowing of transcriptional elongation than allowing Pol II to bypass transcriptional arrest sites (54). In this study, a bulky N-2-acetylaminofluorene-DNA adduct located on the transcribed strand served as an absolute block to elongating Pol II. SII did not increase the ability of Pol II to transcribe through such a lesion. SII did however improve the ability of Pol II to read through a transcriptional pause site created by placing the N-2-acetylaminofluorene adduct on the non-transcribed DNA strand. In another study, N-2-acetylaminofluorene located on the transcribed strand promoted the dissociation of the stalled ternary Pol II·DNA·RNA complex (55). Furthermore, although an elegant in vitro study demonstrated that SII promoted the retrograde (3' to 5') movement of Pol II from a T-T dimer, SII failed to displace stalled Pol II sufficiently to permit repair of the T-T dimer by photolyase (56).
The stalled Pol II complex appears to help recruit the repair apparatus to intragenic damage sites. It also appears to play a role in UV-induced signal transduction (57) and may inhibit basal transcription by binding up nuclear transcription factors such as the TATA box-binding protein, TBP (42). The ability to disassemble this complex, perhaps by degradation of Pol II LS, could be a critical step in the resolution of DNA damage response of the cell and the restoration of basal transcription after DNA repair is completed.
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ACKNOWLEDGEMENTS |
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We thank Errol C. Friedberg, Jan H. J. Hoeijmakers, and Alain J. van Gool for generosity and useful suggestions. We thank Michael Dahmus for a critical review of the manuscript. We also acknowledge Alfred L. Goldberg, Arthur L. Haas, Avram Hershko, Cecile M. Pickart, Irwin A. Rose, and Keith D. Wilkinson for stimulating discussions.
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FOOTNOTES |
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* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by Grant CA73549 from the NCI, National Institutes
of Health, and by Grant 96-59 from the James S. McDonnell Foundation. To whom correspondence should be addressed: Dept. of Pathology, Albert
Einstein College of Medicine, F717N, 1300 Morris Park Ave., Bronx, NY
10461. Tel.: 718-430-2222; Fax: 718-430-8867; E-mail: bregman{at}aecom.yu.edu.
1 The abbreviations used are: E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin-protein ligase; Pol II, RNA polymerase II; NER, nucleotide excision repair; LS, large subunit; TCR, transcription-coupled repair; CS, Cockayne syndrome; CTD, COOH-terminal domain of Pol II LS; IIa, hypophosphorylated Pol II LS; IIo, hyperphosphorylated Pol II LS; mAb, monoclonal antibody; XP, xeroderma pigmentosum; PAGE, polyacrylamide gel electrophoresis; HA, hemagglutinin; WT, wild type.
2 Patturajan, M., Schulte, R. J., Sefton, B. M., Berezney, R., Vincent, M., Bensaude, O., Warren, S. L., and Corden, J. L. (1998) J. Biol. Chem. 273, 4689-4694.
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