Biology Reference
In-Depth Information
higher order structure of chromatin whereas the other four histone proteins
associate with the DNA to form nucleosomes. Each nucleosome is composed of
146 bp of DNA and eight histone molecules, two copies each of histone H2A,
H2B, H3, and H4. The DNA is wrapped around the histones. The N terminus
of each histone contains a number of lysine (K) residues. These residues are
positively charged and these positively charged residues can then interact with
the negatively charged phosphates in DNA. When this positive charge is
neutralized, say by acetylation, then the binding affinity between the histones
and the DNA is reduced. This modification, acetylation, is important in the
regulation of gene transcription.
Little is known about the role of histone modifications in relation to DNA
repair. There are a number of potential modifications that histones could
undergo, such as acetylation, phosphorylation, and ubiquitylation. We review
the most recent studies, which suggest that DNA repair is influenced and
affected by histone modifications. Each of the five DNA repair pathways is
discussed.
I. Histone Modifications of Homologous Recombination Repair
Homologous recombination repair (HRR) is one of two primary pathways
in the repair of DNA double-strand breaks (DSBs). Mechanistically, HRR
utilizes a homologous template, such as a sister chromatid or homologous
chromosome, to repair broken DNA. This process is generally considered
error-free repair, though it may lead to loss of heterozygosity and further
chromosomal instability. HRR functions primarily during the latter portions
of the cell cycle including S and G2, likely because of the presence of homol-
ogous sister chromatids. A complete review of HRR is presented elsewhere in
this text.
HRR plays important roles in multiple oncogenic processes. Its most
infamous role was described over a decade ago in breast cancer. The breast
cancer genes (BRCA) 1 and 2 have since been thoroughly implicated in HRR
and account for a significant proportion of familial inherited breast cancers.
Different portions of the HRR pathway have further been shown to be mutated
in a variety of nonfamilial, somatic, sporadic breast cancers and this is the basis
for the current Phase I, II, and III clinical trials with several molecules that
inhibit a parallel pathway including, specifically, PARP-1.
1
HRR has been
shown to be mutated in a variety of other cancers including leukemia, ovarian,
pancreatic, colon, and uterine cancers. This pathway has also been shown
to be involved in several genetically inherited diseases including ataxia
