Biology Reference
In-Depth Information
NuA4 relaxes the chromatin structure on the region surrounding the DSB;
then this is removed by Sin3p/Rdp3p, which is then followed by the H4Ser1
phosphorylation that inhibits the reacetylation of H4K16 by NuA4.
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g
-H2Ax is phosphorylated after DNA damage. It can be phosphorylated by
ATM and by DNA-dependent protein kinase (DNA PKcs), a protein important
in NHEJ. It has been shown that DNA PKcs can phosphorylate H2Ax within
the nucleosome environment. Studies are conflicting as to whether this phos-
phorylation is influenced by histone acetylation.
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Phosphorylated H2Ax
does not affect nucleosome conformation but it does affect nucleosome stability
as well as impairing histone H1 binding.
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The ubiquitylation of histones can also regulate DNA damage responses.
The pattern appears to be primarily monoubiquitylation rather than polyubi-
quitylation. It appears that ubiquitylation of specific histone residues is re-
quired prior to methylation on other histone residues.
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H2BK123ub is also
required for H3K36 and H3K79 methylation.
There are multiple histone modifications that can occur to aid in this DNA
repair pathway. From the studies, it appears that there is cross talk between
different modifications, and even a specific order of modifications that is
followed. Much more work needs to be done to further define these modifica-
tions in mammalian systems and to understand the way they relate to enhance-
ment or inhibition of the NHEJ DNA repair pathway.
III. Histone Modifications of Nucleotide Excision Repair
The nucleotide excision repair (NER) pathway acts to remove DNA
double-helix distorting lesions, including cyclobutane pyrimidine dimmers
and 6-4 photoproducts, produced by ultraviolet (UV) light, as well as several
kinds of bulky adducts induced by chemical agents such as cisplatin and
4-nitroquinoline oxide, which interfere with base pairing and block DNA
duplication and transcription. NER is divided into two subpathways: global
genomic NER (GG-NER) and transcription-coupled NER (TC-NER). GG-
NER acts mainly on damage in nontranscribed regions of DNA, whereas
TC-NER acts on damage in actively transcribed DNA. The first step of the
NER reaction, the recognition of the DNA lesion, differs considerably between
the GG-NER and TC-NER subpathways. In GG-NER, the xeroderma pig-
mentosa group C (XPC)-hHR23B complex (human homolog of yeast RAD 23)
is responsible for the crucial damage sensing and repair recruitment step. This
step also regulates the rate at which NER is carried out, while in TC-NER, the
first signal for repair activity seems to be the blockage of transcription elongation
by RNA polymerase II in front of DNA lesions.
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The NERmachinery is thought
to be recruited to the stalled RNA polymerase II by the TC-NER-specific
