Biology Reference
In-Depth Information
methylating/alkylating agents, total covalent mono(ADP ribosyl)ation of his-
tones increased by factors of 5-12, while the levels of histone H1-linked mono
(ADP-ribosyl) groups were elevated even more than 30-fold.
73-75
Initial reports
suggested that histone H1 is covalently mono(ADP ribosyl)ated at E2, E14,
E116, or R34, and histone H2B at E2.
76-79
In addition, some other studies have
shown that mono(ADP ribosyl)ation occurs also at glutamic acid residues of
H2A and at arginine residues of H3 and H4.
80
Interestingly, butyrate exposure
elevated basal levels of histone mono(ADP ribosyl)ation on H4 but reduced
subsequent mono(ADP ribosyl)ation of histones initiated by DNA damage,
81
suggesting an antagonistic cross talk of histone mono(ADP ribosyl)ation and
histone acetylation in BER pathways. Still, no nuclear mono(ADP ribosyl)
transferase responsible for these modifications has been identified so far in
higher eukaryotic cells. Because of this missing link, many authors, especially in
the poly(ADP ribose)polymerase field, are quoting these modifications as poly
(ADP ribosyl)ation. Interestingly, a recent study showed evidence that
SIR2-like proteins (a family of
b
-nicotinamide adenine dinucleotide (NAD)-
dependent HDACs) may function as mono(ADP-ribosyl) transferases in these
processes.
82
SIR2-like proteins have been shown to take part in a wide range of
cellular events, including chromosome silencing, chromosome segregation,
DNA repair, DNA recombination, and the determination of life span.
83
TbSIR2RP1, a SIR2-related protein from the protozoan parasite
Trypanosoma
brucei
, has been shown to catalyze mono(ADP ribosyl)ation of histones, par-
ticularly H2A and H2B,
in vitro.
82
Under- or overexpression of TbSIR2RP1
decreased or increased cellular resistance to oxidizing DNA damage, respec-
tively.
82
Remarkably, treatment of trypanosomal nuclei with a DNA-alkylating
agent resulted in a significant increase in the level of histone mono(ADP
ribosyl)ation, in particular H2A and H2B, and a concomitant increase in
chromatin sensitivity to micrococcal nuclease.
82
Both of these responses cor-
related with the level of TbSIR2RP1 expression. Moreover, these studies
supported previous evidence for a link between deacetylation and mono
(ADP ribosyl)ation.
V. DNA Mismatch Repair and Histone Modifications
DNA mismatch repair (MMR) is a highly conserved DNA repair system,
which is essential to all organisms. It has an important role in maintaining
genomic instability. MMR targets mismatches that arise during replication and
homologous recombination (HR), as well as repairing mismatches that occur in
DNA following treatment with alkylating agents.
83,84
In terms of disease, a loss
of the MMR pathway is associated with an increase in genomic instability and
has been linked to hereditary nonpolyposis colorectal cancer.
85,86
