A DNA repair-deficiency disorder is a medical condition due to reduced functionality of
DNA repair.
DNA repair defects can cause an
accelerated aging disease
Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term ''progeroid syndrome'' does not necessarily imply progeria (Hutchinson–Gilford ...
or an increased risk of cancer, or sometimes both.
DNA repair defects and accelerated aging
DNA repair defects are seen in nearly all of the diseases described as
accelerated aging disease
Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term ''progeroid syndrome'' does not necessarily imply progeria (Hutchinson–Gilford ...
, in which various
tissues,
organs or systems of the human body
age
Age or AGE may refer to:
Time and its effects
* Age, the amount of time someone or something has been alive or has existed
** East Asian age reckoning, an Asian system of marking age starting at 1
* Ageing or aging, the process of becoming older ...
prematurely. Because the accelerated aging diseases display different aspects of aging, but never every aspect, they are often called segmental progerias by
biogerontologists.
Human disorders with accelerated aging
*
Ataxia-telangiectasia
*
Bloom syndrome
Bloom syndrome (often abbreviated as BS in literature) is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the '' BLM'' ge ...
*
Cockayne syndrome
Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight ( photo ...
*
Fanconi anemia
Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of no ...
*
Progeria
Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome. A single gene mutation is responsible for progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the Nucleus of the cell ...
(Hutchinson–Gilford progeria syndrome)
*
Rothmund–Thomson syndrome
Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive skin condition.
There have been several reported cases associated with osteosarcoma. A hereditary basis, mutations in the DNA helicase '' RECQL4'' gene, causing problems during init ...
*
Trichothiodystrophy
*
Werner syndrome
Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare, autosomal recessive disord ...
*
Xeroderma pigmentosum
Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun ...
Examples
Some examples of DNA repair defects causing
progeroid syndromes in humans or mice are shown in Table 1.
DNA repair defects distinguished from "accelerated aging"
Most of the DNA repair deficiency diseases show varying degrees of "accelerated aging" or cancer (often some of both).
But elimination of any
gene essential for
base excision repair kills the
embryo—it is too lethal to display symptoms (much less symptoms of cancer or "accelerated aging").
Rothmund-Thomson syndrome and xeroderma pigmentosum display symptoms dominated by vulnerability to cancer, whereas progeria and Werner syndrome show the most features of "accelerated aging".
Hereditary nonpolyposis colorectal cancer
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer (second most common), ovary, ...
(HNPCC) is very often caused by a defective
MSH2 gene leading to defective
mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.
Mismatch ...
, but displays no symptoms of "accelerated aging". On the other hand, Cockayne Syndrome and trichothiodystrophy show mainly features of accelerated aging, but apparently without an increased risk of cancer Some DNA repair defects manifest as
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
rather than as cancer or "accelerated aging". (Also see the "
DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DN ...
" for a discussion of the evidence that DNA damage is the primary underlying cause of aging.)
Debate concerning "accelerated aging"
Some biogerontologists question that such a thing as "accelerated aging" actually exists, at least partly on the grounds that all of the so-called accelerated aging diseases are segmental progerias. Many disease conditions such as
diabetes,
high blood pressure, etc., are associated with increased
mortality
Mortality is the state of being mortal, or susceptible to death; the opposite of immortality.
Mortality may also refer to:
* Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...
. Without reliable
biomarkers of aging
Biomarkers of aging are biomarkers that could predict functional capacity at some later age better than chronological age. Stated another way, biomarkers of aging would give the true "biological age", which may be different from the chronological ...
it is hard to support the claim that a disease condition represents more than accelerated mortality.
Against this position other biogerontologists argue that premature aging
phenotypes are identifiable symptoms associated with mechanisms of molecular damage.
The fact that these phenotypes are widely recognized justifies classification of the relevant diseases as "accelerated aging". Such conditions, it is argued, are readily distinguishable from
genetic disease
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s associated with increased mortality, but not associated with an aging phenotype, such as
cystic fibrosis and
sickle cell anemia. It is further argued that segmental aging phenotype is a natural part of aging insofar as genetic variation leads to some people being more disposed than others to
aging-associated diseases
An aging-associated disease (commonly termed age-related disease, ARD) is a disease that is most often seen with increasing frequency with increasing senescence. They are essentially complications of senescence, distinguished from the aging proc ...
such as
cancer and
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
.
DNA repair defects and increased cancer risk
Individuals with an inherited impairment in
DNA repair capability are often at increased risk of
cancer.
[Bernstein C, Bernstein H, Payne CM, Garewal H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat Res. 2002 Jun;511(2):145-78. Review.] When a
mutation is present in a DNA repair gene, the repair gene will either not be expressed or be expressed in an altered form. Then the repair function will likely be deficient, and, as a consequence, damages will tend to accumulate. Such DNA damages can cause errors during
DNA synthesis
DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs ...
leading to mutations, some of which may give rise to cancer. Germ-line DNA repair mutations that increase the risk of cancer are listed in the Table.
See also
*
Biogerontology
Biogerontology is the sub-field of gerontology concerned with the biological aging process, its evolutionary origins, and potential means to intervene in the process. The term "biogerontology" was coined by S. Rattan, and came in regular use wit ...
*
Degenerative disease
*
DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DN ...
*
Genetic disorder
*
Senescence
References
External links
BRCA - Companion Reviews and Search Terms*
ttps://archive.today/20130211072931/http://www.kidney.de/fmr/Neoplasia%20(Inherited).htm Neoplasia inherited - Companion Reviews and Search Termsbr>
Neoplasia carcinogenesis - Companion Reviews and Search Terms
{{Congenital malformations and deformations of integument
Cancer
DNA repair
Mutation
DNA replication and repair-deficiency disorders
Causes of conditions
Senescence