Biology Reference
In-Depth Information
DSB. Moreover, the levels of H3K36me2 were proportional to the efficiency of
the repair. Therefore, this suggests that H3K36me2 is in a category with
phosphorylated H2Ax and ubiquitylated H2A in that they are all DNA
damage-induced modifications that lead to recruitment of DNA repair proteins
and can then improve the efficiency of DNA repair.
38-42
Many histone modifications have been identified as being related to or
marking sites of active transcription. One such modification is H3K4me3. This
modification is carried out by Set1p methyltransferase and is found in newly
created DSBs.
43
The recruitment was mediated by the RSC chromatin-
remodeling complex, and monoubiquitylation of histone H2B (H2BK123ub)
was also required for the methylation of H3K4. When H3K4me3 was not
present, there was a decrease in NHEJ activity, suggesting that H3K4me3 is
modulating chromatin at the site of DNA damage.
In addition to methylation and phosphorylation, acetylation of histones at
sites of DNA damage can also assist in the repair process. Acetylation by HATs is
an important and critical chromatin modification in DNA repair. Histones H3
andH4 are acetylated on their N-terminal lysines (K5, K8, K12, K16) after DNA
damage and these modifications are essential for NHEJ.
44
In addition, NuA4-
Tip60 HAT acetylates histone H4 at DSBs and improves the repair of the
DSBs.
13,25,44
Chromatin structure and nucleosomes create a barrier to DNA
repair proteins and acetylation of the histones facilitates the relaxation of
chromatin and nucleosome repositioning. The SWI/SNF2 superfamily of remo-
deling complexes (INO80, SWR1, SWI/SNF, and RSC) is also involved in this
relaxation and repositioning. INO80, SWR1, and RSC complexes are also
necessary for Ku70/80 to be recruited to the DSB.
26,45
The RSC complex
localizes to the DSB and also interacts with and recruits Mre11; then ATPase
remodeling occurs which opens the chromatin and allows NHEJ proteins to
gain access to the DSB.
46
CBP and p300 acetylate histones H3 (K18) and H4
(K5, K8, K12, K16) after recruitment to the DSB, and then cooperate with the
SWI/SNF complex to recruit Ku70/80.
47
These studies together suggest that
histone acetylation at a DSB is important for the recruitment of NHEJ proteins
mainly via chromatin relaxation and nucleosome repositioning while at the same
time being important for the recruitment of the early-response NHEJ proteins.
In many studies, a single modification or type of modification appears to be
important for enhancing NHEJ repair of DSBs. However, some studies suggest
that there may be a combination of modifications in a specific order on a single
histone protein. In yeast, acetylation of histone H4 on K16 (H4K16ac) is
important for NHEJ.
48
This modification is removed by the Sin3p/Rdp3p
HDAC complex. Histone H4 is also phosphorylated on serine residue 1 in
response to DNA damage and this is important for NHEJ and inhibits the
acetylation of H4 by NuA4.
49,50
These studies indicate that there are a series of
coordinated histone modifications that occur for DNA repair. H4K16ac by
