Chemistry Reference
In-Depth Information
nucleotide opposite the damage is predominantly incorporated, or error-prone,
whereby an incorrect nucleotide is frequently incorporated opposite the damage.
Consequently, error-free lesion bypass is a mutation-avoiding mechanism, and error-
prone lesion bypass is a mutation-generating mechanism. Several proteins, including
novel Y-family polymerases that have been recently identifi ed in a multitude of
organisms, are involved in DNA damage bypass pathways. Humans have four such
(Y - family) polymerases (Table 6.2 ) - polymerase k, polymerase i, polymerase h , and
Rev1 - each with a unique DNA damage bypass and fi delity profi le. Polymerase h ,
for example, is unique in its ability to replicate through UV-induced cyclobutane
pyrimidine dimers, while polymerase k is ineffi cient at replicating through a T-T
dimer, but can readily extend from mispaired termini. Polymerase i is perhaps the
most unusual with varied effi ciencies and fi delities opposite different template
bases.
Notably, polymerases involved in TLS make up an appreciable fraction of all
known eukaryotic DNA polymerases (Table 6.2). Some of the TLS polymerases are
capable of replicating accurately past certain types of DNA damage. Rev1 does not
have a Greek name since it's not considered a true DNA polymerase; it can insert
only one nucleotide at a time, usually in a template-independent fashion. Polymer-
ases i and k are related to polymerase h but have somewhat different bypass spe-
cifi cities and are not usually error-free. Polymerase q is especially competent at
bypassing AP sites, where it inserts an A residue. Since most AP sites are conse-
quences of purine loss, and A is a purine base, repair by polymerase q is frequently
error - free.
6.3 Specifi c Binding of Repair Proteins to DNA Modifi ed by Antitumour
Platinum Compounds
A number of proteins that are components of various cellular DNA repair systems
bind to DNA modifi ed by antitumour platinum drugs specifi cally (Table 6.3). When
these proteins are absent, repair of DNA damage by platinum complexes is dimin-
ished; sensitivity of cells to the platinum drug is enhanced, which is consistent with
the hypothosis that these proteins modulate biological effects of these metallodrugs.
Some of these proteins initiate specifi c cell signalling pathways.
Recognition of DNA adducts of antitumour platinum compounds by DNA
repair systems has mostly been examined in the case of DNA adducts of cisplatin
and its analogs
cis
- diamminecyclobutanedicarboxylatoplatinum(II)] (carboplatin)
and [(
1R,2R
- diamminocyclohexane)oxalatoplatinum(II)] (oxaliplatin).
Cisplatin binds to DNA, forming mainly intrastrand crosslinks between adja-
cent purine residues (
90%) (1,2 - GG or 1,2 - AG intrastrand crosslinks).
39,40
Other
minor adducts are 1,3-GXG intrastrand crosslinks (X = A, C, T), interstrand
crosslinks (
∼
∼
6% in linear DNA) preferentially between guanine residues in the 5
′
-
- GC sequence
41
and monofunctional lesions. The adducts formed by cisplatin
in DNA affect its secondary structure.
42
The formation of major 1,2-crosslinks of
cisplatin locally unwinds DNA duplex and bends it towards the major groove, expos-
GC/5
′
