Biology Reference
In-Depth Information
Overall, HRR is a complicated process that requires significant alterations
to the chromatin structure to be efficient. In review, this includes insertion of
variants of H2; modifications to all of the core histones and their variants
including the production of phosphorylation, acetylation, and ubiquitylation,
and the recognition of methylation; and the structural remodeling of chromatin
in both the initiation and completion of HRR.
II. Histone Modifications of NHEJ
NHEJ is an error-prone pathway for repairing DNA DSBs. As with homol-
ogous recombination (HR), the first modification that occurs after DNA dam-
age is the phosphorylation on histone H2Ax on Ser139, resulting in
g
-H2Ax.
This modified histone recruits the Ku70/80 complex to the DNA ends where it
binds to the ends and protects the DNA ends from being degraded as well as
acting as a mark of the DSB. The MRN complex is then brought into the DSB.
Together these two complexes then recruit the DNA ligase IV/XRCC4 complex
to religate the ends and repair the break. There are two main barriers for
efficient and effective DNA repair by NHEJ: rapid recruitment of DNA repair
proteins to the site of the DSB; and ease of access to this damage. Chromatin
packed with nucleosomes forms a barrier to these DNA repair proteins so
certain structural issues have to be overcome to allow access for the DNA
repair proteins.
Many studies have been carried out on the function of
g
-H2Ax and its role
for marking a DSB and recruiting DNA repair proteins but there are other
histone modifications that have been identified that may be involved in the
NHEJ repair pathway. These modifications include methylation (me), acetyla-
tion (ac), phosphorylation (p), and ubiquitination (ub) of histones H2A, H2B,
H3, and H4. These histone modifications have been postulated to have two
functions: they can either mark the site of a DNA break to help recruit the
DNA repair proteins or they can be involved in changing and opening
the chromatin structure so that the DNA repair proteins can gain access to
the DSB. As will be discussed, histone modifications do have one or both
functions in NHEJ.
A recent study identified dimethylation of lysine 36 on histone H3
(H3K36me2) as being a mark of DNA damage and subsequent recruitment
of NHEJ proteins.
36
In vitro
studies have identified Metnase, a DNA repair
protein with a histone methylase SET domain, as being the methylase for this
histone H3 residue.
37
Using a model system that allows the generation of a
single DSB in a cell to study NHEJ, it was shown that Metnase could indeed
dimethylate H3K36
in vivo
at/around a DSB, and that the presence of this
histone modification both recruited and stabilized DNA repair proteins at the
