Docstoc

DNA

Document Sample
DNA Powered By Docstoc
					         DNA Repair



Uracil-DNA Glycosylase
    DNA is continually assaulted
by damaging agents (oxygen free
radicals, ultraviolet light, toxic
chemicals).

    Fortunately, the cell has
multiple mechanisms to identify
and correct mutations.
    Yeasts have 50
different enzymes involved
in DNA repair.
    Damage occurs in the form
of deletions and mutations
(changes in the sequence of DNA
bases that make up the genetic
code).
  The DNA
repair process
may be a major
factor in aging,
health, and
longevity.
  An animal's
ability to repair
certain types of
DNA damage is
directly related
to the life span
of its species
  Genetic defects
in DNA repair are
associated with
genetic or familial
susceptibility to
cancer.


 Figure from the Duke University
 Medical Center and the
 Graduate Program in Molecular
 Cancer Biology                    Cell nuclei and chromosomes
 http://mcb.mc.duke.edu/           from a human brain tumor
  Mitochondrial DNA is more
susceptible to damage than
nuclear DNA. Furthermore,
mitochondrial DNA damage
increases exponentially with
age.

   Several diseases that
appear late in life, including
late-onset diabetes, have been
traced to defects in
mitochondria.
    Causes of Mutations
DNA replication
Spontaneous depurination and
deamination
UV light
Oxidation
Chemically induced
DNA Mismatch Repair (E. coli)
How does the cell know which strand
  to repair?
Deoxyadenosine methylase (dam)
Old DNA methylated
New DNA unmethylated
Mismatch repair system cuts
  unmethylated DNA
In eukaryotes the recognition may be
  nicks.
  DNA Repair and Cancer
Do humans have a mismatch repair
 system?
hMSH, human Mut S Homolog
hMLH, human Mut L Homolog
What phenotype would be expected
 from a mutation in hMSH or hMLH?
Hereditary nonpolyposis colon cancer
 (HNPCC), Lynch syndrome II
Depurination and Deamination

Loose A or G

Loose NH2 groups from C
 (forms U)
Base-Excision Repair Pathway
All organisms contain a specific repair
 pathway which removes uracil from
 DNA.
DNA Damage From UV Light
Ionizing radiation causes three types of damage to DNA


Single-strand breaks - mostly sealed by DNA ligase
so don't contribute to lethality

Double-strand breaks - often lethal because can't be
resealed by ligase so degraded by nucleases

Alteration of bases - this type of oxidative damage is
usually lethal because forms a replication barrier at
that site
  uvrABCD Repair System
What would be the phenotype in
 humans from an accumulation of
 thymine dimers in somatic cells?
What would be the phenotype in
 humans from mutations in uvrABCD
 genes?
Xeroderma Pigmentosum (XP)
Disorders Associated with Defective DNA Repair


      Xeroderma pigmentosum (XP)
         Skin photosensitivity; Early onset skin cancer
      Cockayne Syndrome
         Dwarfism; Precociously senile appearance
         Sensitivity to sunlight
      Bloom Syndrome
         Dwarfism, low-birth-weight type;
         Life-threatening infections
         Predisposition to neoplasia
Helicase: Bloom syndrome (genomic instability in
somatic cells, leads to telangiectatic facial erythema,
photosensitivity, dwarfism and other abnormalities)


BRCA1 DNA repair protein Breast and Ovarian cancer,
early onset


MSH2 DNA repair protein Hereditary non-polyposis
colon cancer
Mutations in DNA repair genes lead to an increase
in the frequency of other mutations.
Ataxia-Telangiectasia

Approximately 10% of
children diagnosed with AT
will develop a malignancy in
childhood or early adulthood.

The gene defect in AT patients
allows the formation of a
much higher level of
chromosome translocations.
 Transcription in eukaryotes


Transcription occurs in nucleus,
translation occurs in cytoplasm:

RNA must move across nuclear membrane.
Regulation involves multiple enzymes & proteins
-30 'TATAAAA' (Hogness box) promoter
-50 ~ -500 enhancer sequences control rate
Post-transcriptional processing


poly-A 'tail' (5'-AAAAAA-etc-AAAAAA-3') added to
3' end (Fig.12.10a)
7mG 'cap' (7-methyl guanosine, 7mG) added to 5'
end
splicing of heterogeneous nuclear RNA (hnRNA)
(Fig.12.10b)
up to 90% of transcript is removed
exons are retained ("expressed")
introns are removed ("intervening")
10 ~ 20 exons / 'gene'

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:8
posted:12/1/2011
language:English
pages:25