PROBLEM STATEMENT:
1. Unrepaired DNA Damage leads to mutation which are changes in DNA sequences
2. Inherited defects in DNA repair increase susceptibility to diseases
3. Accumulated DNA damage induces contributing to aging and organ dysfunction
DNA damage is well recognized as a critical factor in cancer
development and progression. DNA lesions create an abnormal
nucleotide or nucleotide fragment, causing a break in one or both chains
of the DNA strand. When DNA damage occurs, the possibility of
generated mutations increases. Genomic instability is one of the most
important factors that lead to cancer development. DNA repair
pathways perform the essential role of correcting the DNA lesions that
occur from DNA damaging agents or carcinogens, thus maintaining
genomic stability. Inefficient DNA repair is a critical driving force behind
cancer establishment, progression and evolution. A thorough
understanding of DNA repair mechanisms in cancer will allow for better
therapeutic intervention. In this review we will discuss the relationship
between DNA damage/repair mechanisms and cancer, and how we can
target these pathways.
Some diseases are caused by mutations that are inherited from the
parents and are present in an individual at birth, like sickle cell
disease. Other diseases are caused by acquired mutations in a gene or
group of genes that occur during a person's life. Such mutations are
not inherited from a parent, but occur either randomly or due to some
environmental exposure (such as cigarette smoke). These include
many cancers, as well as some forms of neurofibromatosis.
DNA damage has been long recognized as causal factor for cancer
development. When erroneous DNA repair leads to mutations or
chromosomal aberrations affecting oncogenes and tumor suppressor
genes, cells undergo malignant transformation resulting in cancerous
growth. Genetic defects can predispose to cancer: mutations in distinct
DNA repair systems elevate the susceptibility to various cancer types.
However, DNA damage not only comprises a root cause for cancer
development but also continues to provide an important avenue for
chemo- and radiotherapy. Since the beginning of cancer therapy,
genotoxic agents that trigger DNA damage checkpoints have been
applied to halt the growth and trigger the apoptotic demise of cancer
cells. DNA damage is a common event in cells, resulting from both
internal and external factors. The maintenance of genomic integrity is
vital for cellular function and physiological processes. The inadequate
repair of DNA damage results in the genomic instability, which has
been associated with the development and progression of various
human diseases. Since all organisms are continuously exposed to
exogenous and endogenous DNA damaging agents, mechanisms of
repair of DNA lesions are necessary to maintain the integrity of the
genome. Studies of the cellular defects in human inherited diseases
with deficiencies in DNA repair have given new insights into these
processes. Nucleotide excision repair is an important DNA repair
pathway in which several types of DNA lesions are removed by a multi-
step enzymatic process. This repair mechanism is deficient in the rare
disease xeroderma pigmentosum (XP), which results in extreme
sensitivity to ultraviolet light (UV) and development of UV-induced skin
tumors at an early age. There are several genetic complementation
groups of XP. The genes that are mutated in some of the XP
complementation groups have been cloned and the functions of the
encoded proteins are being characterised. Several types of DNA lesions
are removed more rapidly from active genes than from other regions
of DNA. This preferential repair of active genes is deficient in
Cockayne's syndrome, which is characterised by developmental
abnormalities and UV-sensitivity but no marked increase in cancer
incidence. Other syndromes associated with increased sensitivity to
certain DNA damaging agents where no defect in DNA repair has been
defined include Fanconi's anemia (sensitivity to DNA crosslinking
agents), hereditary dysplastic nevus syndrome (sensitivity to UV) and
ataxia-telangiectasia (sensitivity to ionizing radiation). Cancer is
considered to be a disease of genome instability and mutation caused
by errors in DNA damage repair[5,46,47]. Cytogenetics analysis of
cancer cells often reveals chromosomal instability, copy number
alterations, and expansions or contractions of repetitive microsatellite
sequences[46]. Evidence that errors in DNA damage maintenance are
linked to cancer development lies in the fact that mutations in several
DDR genes are linked to several cancer syndromes [Table 1].
Point mutations in the HR pathway
genes BRCA1 and BRCA2 predispose women to hereditary breast and
ovarian cancer (HBOC) syndrome[14,48]. HBOC accounts for up to 10%
of breast cancer cases - individuals that are heterozygous carriers
of BRCA1/2 mutations have a 40-80% lifetime risk of developing breast
cancer[49] while male patients who harbor BRCA1/2 mutations have an
increased risk of developing breast, pancreas, and prostate
cancers[50-52]. Familial mutations in HR pathway genes BACH1,
PALB2, and RAD51C have also been identified in 3% of familial breast
cancer patients and confer a 2-fold increased risk of developing breast
cancer[53], while mutations in key genes involved in DSB repair
including CHK2, ATM, NBS1, and RAD50 have been shown to also
confer a 2-fold increased risk of breast cancer[54].
Heterozygous mutations in MMR pathway genes MLH1, MSH2, MSH6,
and PMS2 have been linked to HNPCC, or Lynch Syndrome[55].
Patients present primarily with colorectal cancer but also have an
increased predisposition to developing endometrial, ovarian, gastric,
and renal carcinomas.
FA is a genetic syndrome characterized by mutations in 13 FA genes
(FANCA to FANCV) involved in the ICL repair pathway. Monoallelic
inactivation of FANCD1(also known as BRCA2) leads to adult HBOC
cancer predisposition syndrome with an increased lifetime risk of
breast cancer by 50% and a 15% increased lifetime risk of ovarian
cancer (reviewed in Nalepa & Clapp)[56]. A review of The Cancer
Genome Atlas has identified acquired mutations, epigenetic silencing,
and copy number variations in FA genes have been identified in
patients with a variety of malignancies