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tumor development was absent in a group of 22 control animals [26]. The high
frequency of hepatocellular adenomas indicates that the liver accumulates high
levels of NER lesions or is particularly sensitive to them, a notion that will be of
importance in the discussion of the phenotype of ERCCl -deficient mice later. Oral
administration of the carcinogen B[a]P to XPA mice induced mainly lymphomas
with reduced latency and higher frequency than wild-type mice, establishing XP as
a disease with increased risk to internal tumors. To study the correlation between
carcinogenesis and mutagenesis, XPA mice were intercrossed with transgenic mice
carrying multiple copies of a plasmid containing the lacZ marker gene in their
genome. After oral administration of B[a]P, plasmids were rescued from the
genome and mutation frequencies in the lacZ gene were detelmined, revealing a
con'Clation between lymphoma development and increased mutation fi:equency in
lymphogenic tissue of XPA mice [26]. Similarly, mutagenesis at the endogenous
hprtlocus in B[a]P-h'eated XPA mice correlated with Iymfomagenesis [27].
Because XPA mice are sensitive to a broad range of genotoxic agents (including
UV, B[a]P, PhIP, N-OH-AAF, mitomycin C, cis-platin), they are particularly suited
for screening genotoxic agents. Therefore, this mouse mutant is now evaluated in a
program of the phannaceutical industry and US government with various
carcinogenic and genotoxic compounds, honnones and inununo-suppressing
carcinogens. Together with p53+1- mice, transgenic II-ras mice, and several other
models, XPA mice are considered as an alternative model for testing carcinogenic
and inununo-suppressive compounds. The reader is refened for more information
about the test program to web-site Http://ntp-server.lliehs.nih.gov/Main---'pages/
transgen/lLSItbl2.hhnl.
CONSEQUENCES OF MULTI-FUNCTIONALITY OF NER PROTEINS
Besides their role in nucleotide excision repair, many individual NER proteins are
simultaneously also involved in other cellular processes. As mentioned before, the
TCR subpathway accomplishes preferential repair of transcription-blocking lesions
from transcribed DNA sequences, involving the CSA and CSB proteins. Recently,
direct interaction between the CSB protein and the (elongating) RNApolII complex
has been observed [28]. This implies that a CSB defect may affect the process of
transcription elongation as welL The coupling between NER and transcription
appeared even more intimate when it was discovered that the XPB and XPD genes
encode the helicase subunits of the dual functional DNA repair/basal transcription
factor TFIIH [29, 30] implying that XPB and XPD are also basal transcription
initiation proteins. Other NER components are involved in mitotic recombination
and replication or have likely connections with base excision repair, ubiquitination
and cell cycle regulation (see Table II for an overview). Predictably, the close link
of NER with so many different processes will have multiple effects on the
physiology of an organism when any of these factors is defective. In the next
36 Chapter 2