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DNA Damage & Repair mechanisms
Dr. Nagabhushan CharantimathPhD
Asst Professor, Dept of Zoology,
Vijayanagara Sri Krishnadevaraya University, Ballari, Karnataka, INDIA
2/22/2024 1
Introduction
2
• DNA in the living cell is subjected to many
chemical alterations.
• The genetic information encoded in the DNA has to
remain uncorrupted
• Any chemical changes must be corrected.
• A failure to repair DNA produces a mutation.
2/22/2024
2/22/2024 3
Agents damaging DNA
4
Radiations
Chemicals in the environment
Oxidative damage (from free radicals) ROS
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Agents damaging DNA
5
1. Radiations
Ionizing radiation such as gamma rays and X-rays
Ultraviolet rays, especially the UV-C rays (~260 nm) that
are absorbed strongly by DNA but also the longer-
wavelength UV-B that penetrates the ozone shield.
2/22/2024
Agents damaging DNA
6
2. Chemicals in the environment
Highly reactive oxygen radicals produced during normal
cellular respiration as well as by other biochemical pathways
Aromatic hydrocarbons, (cigarette smoke)
Plant and microbial products (aflatoxin from moldy
peanuts)
Chemicals used in chemotherapy, (of cancer)
2/22/2024
Types of DNA damage
7
S.No. Type of Damage Examples
1) Single-base alteration A.Depurination
B.Deamination of cytosine to uracil
C.Deamination of adenine to hypoxanthine
D.Alkylation of base
E.Insertion or deletion of nucleotide
F.Base-analog incorporation
2) Two-base alterations A. UV light–induced T-T (pyrimidine) dimer
B. Bifunctional Alkylating agent cross-linkage
3) Chain breaks A. Ionizing radiation
B. Radioactive disintegration of backbone element
C. Oxidative free radical formation
4) Cross-linkage A. Between bases in same or opposite strands
B. Between DNA and protein molecules (eg, histones)
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DNA Repair
DNA repair can be grouped into two major functional
categories:
A) Direct Damage reversal B) Excision of DNA damage
8
2/22/2024
A) Direct Damage Reversal
9
The direct reversal of DNA damage is the simplest repair
mechanism that involves a single polypeptide chain, with
enzymatic properties which binds to the damage and restores the DNA
genome to its normal state in a single-reaction step. The major
polypeptides involved in this pathway are:
i) DNA photolyase is responsible for removing cyclobutane pyrimidine
dimers from DNA in a light-dependent process called as photo
reactivation (not in all organisms)
2/22/2024
ii) O6-methylguanine-DNA
methyltransferase I and II
(MGMT), also called DNA-
alkyltransferases,
remove the modified bases like
O6- alkyl-guanine and
O4-alkyl-thymine.
The photolyase protein is not
found in all living cells. However,
the DNA-alkyltransferases
are widespread in nature.
10
2/22/2024
B) Excision of DNA damage
11
i) Base excision repair (BER)
ii) Nucleotide excision repair (NER),
iii) Mismatch repair (MMR) and
iv) Strand break repairs.
•
In these reactions a nucleotide segment containing base
damage, double-helix distortion or mispaired bases are
replaced by the normal nucleotide sequence in a new DNA
polymerase synthesis process.
These pathways have been characterized in both bacterial
and eukaryotic organisms.
2/22/2024
i) Base Excision Repair (BER)
12
• Case 1: BER is initiated by DNA glycosylases, which
catalyze the hydrolysis of the N-glycosidic bonds,
linking particular types of chemically altered bases to
the deoxyribose-phosphate backbone.
• DNA damage is excised as free bases, generating sites
of base loss called apurinic or apyrimidinic (AP)
sites.
2/22/2024
i) Base excision repair (BER)
ii) Nucleotide excision repair (NER),
iii) Mismatch repair (MMR) and
iv) Strand break repairs.
13
The AP sites are substrates for AP endonucleases.
These enzymes produce incisions in duplex DNA as a result of the
hydrolysis of a phosphodiester bond immediately at 5' or 3' ends.
The ribose-phosphate backbone is then removed from the DNA
through the action of a specific exonuclease called
deoxy ribo-phospho-di-esterase or dRpase.
Finally, the DNA polymerase and a Ligase catalyze the incorporation
of a specific deoxyribonucleotide into the repaired site, enabling
correct base pairing.
2/22/2024
Base excision-repair of DNA
case2: The enzyme uracil DNA
glycosylase removes the uracil
created by spontaneous
deamination of cytosine in the
DNA.
An endonuclease cuts the
backbone near the defect.
An endonuclease removes a few
bases.
The defect is filled in by the action
of a DNA polymerase and the
strand is rejoined by a ligase.
14
2/22/2024
ii) Nucleotide excision repair (NER)
15
2/22/2024
i) Base excision repair (BER)
ii) Nucleotide excision repair (NER),
iii) Mismatch repair (MMR) and
iv) Strand break repairs.
16
This mechanism is used to replace regions of damaged
DNA up to 30 bases in length.
Chemical causes induces the formation of cyclobutane
pyrimidine-pyrimidine dimers, and
smoking causes formation of alpha pyrene-guanine adducts.
Ionizing radiation, cancer chemotherapeutic agents, and other
chemicals cause base modification, strand breaks, cross-linkage
between bases on opposite strands or between DNA and protein,
and numerous other defects.
These are repaired by NER
2/22/2024
17
• NER is a much more complex biochemical process
than BER, especially in eukaryotic cells.
• Several gene products are required in a multiple step
process, during which the ordered assembly of DNA
proteins provides an enzymatic complex that
discriminates damaged from undamaged DNA.
2/22/2024
(NER)
In eukaryotic cells the enzymes cut
between the third to fifth
phosphodiester bond 3' from the
lesion, and on the 5' side the cut is
somewhere between the twenty-first
and twenty-fifth bonds.
Thus, a fragment of DNA 27–29
nucleotides long is excised.
After the strand is removed it is
replaced, again by exact base pairing,
through the action of another
polymerase,and the ends are joined
to the existing strands by DNA ligase.
18
2/22/2024
• In Escherichia
coli there are three specific
proteins, called Uvr-A, Uvr-B
& Uvr-C, are involved in
lesion recognition and
endonuclease incision.
This fragment is released
by Uvr-D helicase action,
generating a gap that is
finally submitted to repair
synthesis.
19
2/22/2024
Transcription-Coupled NER
20
• Nucleotide-excision repair proceeds most rapidly
on genes being actively transcribed on the DNA
strand that is serving as the template for
transcription.
• If RNA polymerase II, is tracking along the template
(antisense strand), encounters a damaged base, it
can recruit other proteins, to make a quick fix before
it moves on to complete transcription of the gene.
2/22/2024
iii) Mismatch repair (MMR)
21
• Mismatch repair corrects errors made when DNA is copied.
• For example, a C could be inserted opposite an A, or the
polymerase could slip or stutter and insert two to five extra
unpaired bases.
• Specific proteins scan the newly synthesized DNA, using
adenine methylation within a GATC sequence as the point of
reference.
• The template strand is methylated, and the newly
synthesized strand is not methylated.
2/22/2024
i) Base excision repair (BER)
ii) Nucleotide excision repair (NER),
iii) Mismatch repair (MMR) and
iv) Strand break repairs.
22
• This difference allows the repair enzymes to identify the
strand that contains the errant nucleotide which requires
replacement.
• If a mismatch or small loop is found, a GATC endonuclease
cuts the strand bearing the mutation at a site corresponding
to the GATC.
• An exonuclease then digests this strand from the GATC through
the mutation, thus removing the faulty DNA. This can occur
from either end if the defect is bracketed by two GATC sites.
• This defect is then filled in by normal cellular enzymes
according to base pairing rules.
2/22/2024
• This mechanism corrects a
single mismatch base pair (eg.
C to A rather than T to A) or a
short region of unpaired DNA.
The defective region is
recognized by an
endonuclease that makes a
single-strand cut at an adjacent
methylated GATC sequence.
The DNA strand is removed
through the mutation,
replaced, and religated.
23
2/22/2024
• In E coli, three proteins (Mut-S, Mut- L,
and Mut-H) are required for
recognition of the mutation and nicking
of the strand.
• Other cellular enzymes, including ligase,
polymerase, and SSBs, remove and
replace the strand.
• The process is more complicated in
mammalian cells, as about six proteins
are involved in the first step.
• Faulty mismatch repair has been linked
to hereditary nonpolyposis colon cancer
(HNPCC), one of the most common
inherited cancers.
24
2/22/2024
iv) Repairing Strand Breaks
25
• Ionizing radiation and certain chemicals can produce both
single-strand breaks (SSBs) and double-strand breaks (DSBs)
in the DNA backbone.
Single-Strand Breaks (SSBs)
• Breaks in a single strand of the DNA molecule are repaired
using the same enzyme systems that are used in Base-
Excision Repair (BER).
2/22/2024
i) Base excision repair (BER)
ii) Nucleotide excision repair (NER),
iii) Mismatch repair (MMR) and
iv) Strand break repairs.
26
Double-Strand Break Repair
There are two mechanisms by which the cell
attempts to repair a complete break in a DNA molecule:
1) Direct joining of the broken ends. This requires proteins that
recognize and bind to the exposed ends and bring them
together for ligating. This type of joining is also called
Nonhomologous End-Joining (NHEJ) using a protein called Ku.
2/22/2024
27
Errors in direct joining may be a cause of the various
translocations that are associated with cancers.
Examples:
• Burkitt's lymphoma
• Philadelphia chromosome in chronic myelogenous
leukemia (CML)
• B-cell leukemia
2/22/2024
28
2) Homologous Recombination: Here the broken ends are
repaired using the information on the intact sister
chromatid or the homologous chromosome.
Two of the proteins used in homologous
recombination are encoded by the genes BRCA1
and BRCA2.
Inherited mutations in these genes predispose women to breast
and ovarian cancers.
2/22/2024
Meiosis also involves DSBs
Recombination between
homologous chromosomes
in meiosis I also involves
the formation of DSBs.
Thus in Meiosis I with the
alignment of homologous
sequences provides a
mechanism for repairing
damaged DNA.
29
2/22/2024
Diseases associated with defective DNA repair system
30
•
•
•
•
•
•
•
•
•
Ataxia telangiectasia
Bloom syndrome
Cockayne's syndrome
Progeria (Hutchinson-Gilford Progeria syndrome)
Rothmund-Thomson syndrome
Trichothiodystrophy
Werner syndrome
Xeroderma pigmentosum
Hereditary non polyposis colon cancer.
2/22/2024
Ataxia-telangiectasia (A-T)
• Ataxia-telangiectasia (A-T) is an autosomal
recessive, complex, multisystem disorder
characterized by progressive neurologic
impairment, cerebellar ataxia, variable
immunodeficiency with susceptibility to
sinopulmonary infections, impaired organ
maturation, ocular and cutaneous
telangiectasia and a predisposition to
malignancy.
31
2/22/2024
Bloom syndrome
Head is disproportionately small, Striking paucity
of subcutaneous fat tissue throughout infancy
and childhood, and A redness of the cheeks and
nose that characteristically makes its appearance
in infancy after sun exposure.
Chronic obstructive lung disease, Diabetes
mellitus and malignancies of varied types are
some of the common complications of Bloom
syndrome.
32
2/22/2024
Cockayne's syndrome
It is also called Weber-Cockayne syndrome, or Neill-
Dingwall Syndrome. It is a rare autosomal recessive
congenital disorder characterized by growth failure,
impaired development of the nervous system,
abnormal sensitivity to sunlight (photosensitivity),
and premature aging.
Hearing loss and eye abnormalities (pigmentary
retinopathy) are other common features, but problems
with any or all of the internal organs are possible.
It is associated with a group of disorders called
leukodystrophies.
33
2/22/2024
Tricho-thio-dystrophy
• Brittle hair, rough skin and extreme
photosensitivity are the characteristic
features. The trichothiodystrophies (TTD) are
named primarily for the hair sulphur
deficiency which is their most specific
feature and which leads to brittleness of the
hair.
• There is defect in DNA excision repair
system along with other defects.
Biochemistry for Medics-Lecture Notes 31
34
Rothmund-Thomson syndrome
The common clinical findings are-
•
•
•
•
• Sun-sensitive rash with
telangiectasias
Juvenile cataract
Congenital bone defects, including short stature
and anomalies such as absent thumbs
Hair growth problems (absence of eyelashes,
eyebrows and/or hair)
Osteosarcoma
35
2/22/2024
Progeria
Progeria (Hutchinson-Gilford Progeria Syndrome) is an
extremely rare genetic disorder that causes the affected
individual to undergo advanced aging at an early age.
The symptoms closely resemble aging and include wrinkles,
hair loss, and delayed growth.
Affected individuals have normal development up to 18
months and suddenly stop gaining weight and display
stunted height.
As the individual ages, Progeria becomes more severe with
an average life expectancy of 12 years.
36
2/22/2024
Werner syndrome (Adult Progeria)
sy
synd
ndro
rom
me
e
Werner syndrome is a hereditary condition associated with premature aging
and an increased risk of cancer and other diseases. The signs of Werner
syndrome usually develop in the teenage years.
A person with Werner syndrome does not have the usual growth spurt typical of
a teenager and is shorter on average. Signs of aging, including gray hair and hair
loss as early as in 20s.
Biochemistry for Medics-Lecture Notes 34
37
Xeroderma pigmentosum (XP)
•
•
•
•
•
Xeroderma pigmentosum (XP) is an
autosomal recessive genetic disease.
The clinical syndrome includes marked
sensitivity to sunlight (ultraviolet) with
subsequent formation of multiple skin
cancers and premature death.
The risk of developing skin cancer is
increased 1000- to 2000-fold.
The inherited defect seems to involve the repair
of damaged DNA, particularly thymine dimers.
Cells cultured from patients with xeroderma
pigmentosum exhibit low activity for the
nucleotide excision-repair process.
38
2/22/2024
Acknowledgement
39
• http://highered.mcgraw- hill.com/sites/0072556781/student_view0/ch
apter11/animation_quiz_5.html
• http://highered.mcgraw- hill.com/sites/dl/free/0072835125/126997/an
imation34.html
• Original script : Dr Namrata Chhabra, Biochemistry for medics
• http://highered.mcgraw- hill.com/sites/dl/free/0072835125/126997/an
imation33.html
• Images courtesty: google
2/22/2024
2/22/2024 40
Thank you
Discussion time

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DNA damage and repair mechanism

  • 1. DNA Damage & Repair mechanisms Dr. Nagabhushan CharantimathPhD Asst Professor, Dept of Zoology, Vijayanagara Sri Krishnadevaraya University, Ballari, Karnataka, INDIA 2/22/2024 1
  • 2. Introduction 2 • DNA in the living cell is subjected to many chemical alterations. • The genetic information encoded in the DNA has to remain uncorrupted • Any chemical changes must be corrected. • A failure to repair DNA produces a mutation. 2/22/2024
  • 4. Agents damaging DNA 4 Radiations Chemicals in the environment Oxidative damage (from free radicals) ROS 2/22/2024
  • 5. Agents damaging DNA 5 1. Radiations Ionizing radiation such as gamma rays and X-rays Ultraviolet rays, especially the UV-C rays (~260 nm) that are absorbed strongly by DNA but also the longer- wavelength UV-B that penetrates the ozone shield. 2/22/2024
  • 6. Agents damaging DNA 6 2. Chemicals in the environment Highly reactive oxygen radicals produced during normal cellular respiration as well as by other biochemical pathways Aromatic hydrocarbons, (cigarette smoke) Plant and microbial products (aflatoxin from moldy peanuts) Chemicals used in chemotherapy, (of cancer) 2/22/2024
  • 7. Types of DNA damage 7 S.No. Type of Damage Examples 1) Single-base alteration A.Depurination B.Deamination of cytosine to uracil C.Deamination of adenine to hypoxanthine D.Alkylation of base E.Insertion or deletion of nucleotide F.Base-analog incorporation 2) Two-base alterations A. UV light–induced T-T (pyrimidine) dimer B. Bifunctional Alkylating agent cross-linkage 3) Chain breaks A. Ionizing radiation B. Radioactive disintegration of backbone element C. Oxidative free radical formation 4) Cross-linkage A. Between bases in same or opposite strands B. Between DNA and protein molecules (eg, histones) 2/22/2024
  • 8. DNA Repair DNA repair can be grouped into two major functional categories: A) Direct Damage reversal B) Excision of DNA damage 8 2/22/2024
  • 9. A) Direct Damage Reversal 9 The direct reversal of DNA damage is the simplest repair mechanism that involves a single polypeptide chain, with enzymatic properties which binds to the damage and restores the DNA genome to its normal state in a single-reaction step. The major polypeptides involved in this pathway are: i) DNA photolyase is responsible for removing cyclobutane pyrimidine dimers from DNA in a light-dependent process called as photo reactivation (not in all organisms) 2/22/2024
  • 10. ii) O6-methylguanine-DNA methyltransferase I and II (MGMT), also called DNA- alkyltransferases, remove the modified bases like O6- alkyl-guanine and O4-alkyl-thymine. The photolyase protein is not found in all living cells. However, the DNA-alkyltransferases are widespread in nature. 10 2/22/2024
  • 11. B) Excision of DNA damage 11 i) Base excision repair (BER) ii) Nucleotide excision repair (NER), iii) Mismatch repair (MMR) and iv) Strand break repairs. • In these reactions a nucleotide segment containing base damage, double-helix distortion or mispaired bases are replaced by the normal nucleotide sequence in a new DNA polymerase synthesis process. These pathways have been characterized in both bacterial and eukaryotic organisms. 2/22/2024
  • 12. i) Base Excision Repair (BER) 12 • Case 1: BER is initiated by DNA glycosylases, which catalyze the hydrolysis of the N-glycosidic bonds, linking particular types of chemically altered bases to the deoxyribose-phosphate backbone. • DNA damage is excised as free bases, generating sites of base loss called apurinic or apyrimidinic (AP) sites. 2/22/2024 i) Base excision repair (BER) ii) Nucleotide excision repair (NER), iii) Mismatch repair (MMR) and iv) Strand break repairs.
  • 13. 13 The AP sites are substrates for AP endonucleases. These enzymes produce incisions in duplex DNA as a result of the hydrolysis of a phosphodiester bond immediately at 5' or 3' ends. The ribose-phosphate backbone is then removed from the DNA through the action of a specific exonuclease called deoxy ribo-phospho-di-esterase or dRpase. Finally, the DNA polymerase and a Ligase catalyze the incorporation of a specific deoxyribonucleotide into the repaired site, enabling correct base pairing. 2/22/2024
  • 14. Base excision-repair of DNA case2: The enzyme uracil DNA glycosylase removes the uracil created by spontaneous deamination of cytosine in the DNA. An endonuclease cuts the backbone near the defect. An endonuclease removes a few bases. The defect is filled in by the action of a DNA polymerase and the strand is rejoined by a ligase. 14 2/22/2024
  • 15. ii) Nucleotide excision repair (NER) 15 2/22/2024 i) Base excision repair (BER) ii) Nucleotide excision repair (NER), iii) Mismatch repair (MMR) and iv) Strand break repairs.
  • 16. 16 This mechanism is used to replace regions of damaged DNA up to 30 bases in length. Chemical causes induces the formation of cyclobutane pyrimidine-pyrimidine dimers, and smoking causes formation of alpha pyrene-guanine adducts. Ionizing radiation, cancer chemotherapeutic agents, and other chemicals cause base modification, strand breaks, cross-linkage between bases on opposite strands or between DNA and protein, and numerous other defects. These are repaired by NER 2/22/2024
  • 17. 17 • NER is a much more complex biochemical process than BER, especially in eukaryotic cells. • Several gene products are required in a multiple step process, during which the ordered assembly of DNA proteins provides an enzymatic complex that discriminates damaged from undamaged DNA. 2/22/2024
  • 18. (NER) In eukaryotic cells the enzymes cut between the third to fifth phosphodiester bond 3' from the lesion, and on the 5' side the cut is somewhere between the twenty-first and twenty-fifth bonds. Thus, a fragment of DNA 27–29 nucleotides long is excised. After the strand is removed it is replaced, again by exact base pairing, through the action of another polymerase,and the ends are joined to the existing strands by DNA ligase. 18 2/22/2024
  • 19. • In Escherichia coli there are three specific proteins, called Uvr-A, Uvr-B & Uvr-C, are involved in lesion recognition and endonuclease incision. This fragment is released by Uvr-D helicase action, generating a gap that is finally submitted to repair synthesis. 19 2/22/2024
  • 20. Transcription-Coupled NER 20 • Nucleotide-excision repair proceeds most rapidly on genes being actively transcribed on the DNA strand that is serving as the template for transcription. • If RNA polymerase II, is tracking along the template (antisense strand), encounters a damaged base, it can recruit other proteins, to make a quick fix before it moves on to complete transcription of the gene. 2/22/2024
  • 21. iii) Mismatch repair (MMR) 21 • Mismatch repair corrects errors made when DNA is copied. • For example, a C could be inserted opposite an A, or the polymerase could slip or stutter and insert two to five extra unpaired bases. • Specific proteins scan the newly synthesized DNA, using adenine methylation within a GATC sequence as the point of reference. • The template strand is methylated, and the newly synthesized strand is not methylated. 2/22/2024 i) Base excision repair (BER) ii) Nucleotide excision repair (NER), iii) Mismatch repair (MMR) and iv) Strand break repairs.
  • 22. 22 • This difference allows the repair enzymes to identify the strand that contains the errant nucleotide which requires replacement. • If a mismatch or small loop is found, a GATC endonuclease cuts the strand bearing the mutation at a site corresponding to the GATC. • An exonuclease then digests this strand from the GATC through the mutation, thus removing the faulty DNA. This can occur from either end if the defect is bracketed by two GATC sites. • This defect is then filled in by normal cellular enzymes according to base pairing rules. 2/22/2024
  • 23. • This mechanism corrects a single mismatch base pair (eg. C to A rather than T to A) or a short region of unpaired DNA. The defective region is recognized by an endonuclease that makes a single-strand cut at an adjacent methylated GATC sequence. The DNA strand is removed through the mutation, replaced, and religated. 23 2/22/2024
  • 24. • In E coli, three proteins (Mut-S, Mut- L, and Mut-H) are required for recognition of the mutation and nicking of the strand. • Other cellular enzymes, including ligase, polymerase, and SSBs, remove and replace the strand. • The process is more complicated in mammalian cells, as about six proteins are involved in the first step. • Faulty mismatch repair has been linked to hereditary nonpolyposis colon cancer (HNPCC), one of the most common inherited cancers. 24 2/22/2024
  • 25. iv) Repairing Strand Breaks 25 • Ionizing radiation and certain chemicals can produce both single-strand breaks (SSBs) and double-strand breaks (DSBs) in the DNA backbone. Single-Strand Breaks (SSBs) • Breaks in a single strand of the DNA molecule are repaired using the same enzyme systems that are used in Base- Excision Repair (BER). 2/22/2024 i) Base excision repair (BER) ii) Nucleotide excision repair (NER), iii) Mismatch repair (MMR) and iv) Strand break repairs.
  • 26. 26 Double-Strand Break Repair There are two mechanisms by which the cell attempts to repair a complete break in a DNA molecule: 1) Direct joining of the broken ends. This requires proteins that recognize and bind to the exposed ends and bring them together for ligating. This type of joining is also called Nonhomologous End-Joining (NHEJ) using a protein called Ku. 2/22/2024
  • 27. 27 Errors in direct joining may be a cause of the various translocations that are associated with cancers. Examples: • Burkitt's lymphoma • Philadelphia chromosome in chronic myelogenous leukemia (CML) • B-cell leukemia 2/22/2024
  • 28. 28 2) Homologous Recombination: Here the broken ends are repaired using the information on the intact sister chromatid or the homologous chromosome. Two of the proteins used in homologous recombination are encoded by the genes BRCA1 and BRCA2. Inherited mutations in these genes predispose women to breast and ovarian cancers. 2/22/2024
  • 29. Meiosis also involves DSBs Recombination between homologous chromosomes in meiosis I also involves the formation of DSBs. Thus in Meiosis I with the alignment of homologous sequences provides a mechanism for repairing damaged DNA. 29 2/22/2024
  • 30. Diseases associated with defective DNA repair system 30 • • • • • • • • • Ataxia telangiectasia Bloom syndrome Cockayne's syndrome Progeria (Hutchinson-Gilford Progeria syndrome) Rothmund-Thomson syndrome Trichothiodystrophy Werner syndrome Xeroderma pigmentosum Hereditary non polyposis colon cancer. 2/22/2024
  • 31. Ataxia-telangiectasia (A-T) • Ataxia-telangiectasia (A-T) is an autosomal recessive, complex, multisystem disorder characterized by progressive neurologic impairment, cerebellar ataxia, variable immunodeficiency with susceptibility to sinopulmonary infections, impaired organ maturation, ocular and cutaneous telangiectasia and a predisposition to malignancy. 31 2/22/2024
  • 32. Bloom syndrome Head is disproportionately small, Striking paucity of subcutaneous fat tissue throughout infancy and childhood, and A redness of the cheeks and nose that characteristically makes its appearance in infancy after sun exposure. Chronic obstructive lung disease, Diabetes mellitus and malignancies of varied types are some of the common complications of Bloom syndrome. 32 2/22/2024
  • 33. Cockayne's syndrome It is also called Weber-Cockayne syndrome, or Neill- Dingwall Syndrome. It is a rare autosomal recessive congenital disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), and premature aging. Hearing loss and eye abnormalities (pigmentary retinopathy) are other common features, but problems with any or all of the internal organs are possible. It is associated with a group of disorders called leukodystrophies. 33 2/22/2024
  • 34. Tricho-thio-dystrophy • Brittle hair, rough skin and extreme photosensitivity are the characteristic features. The trichothiodystrophies (TTD) are named primarily for the hair sulphur deficiency which is their most specific feature and which leads to brittleness of the hair. • There is defect in DNA excision repair system along with other defects. Biochemistry for Medics-Lecture Notes 31 34
  • 35. Rothmund-Thomson syndrome The common clinical findings are- • • • • • Sun-sensitive rash with telangiectasias Juvenile cataract Congenital bone defects, including short stature and anomalies such as absent thumbs Hair growth problems (absence of eyelashes, eyebrows and/or hair) Osteosarcoma 35 2/22/2024
  • 36. Progeria Progeria (Hutchinson-Gilford Progeria Syndrome) is an extremely rare genetic disorder that causes the affected individual to undergo advanced aging at an early age. The symptoms closely resemble aging and include wrinkles, hair loss, and delayed growth. Affected individuals have normal development up to 18 months and suddenly stop gaining weight and display stunted height. As the individual ages, Progeria becomes more severe with an average life expectancy of 12 years. 36 2/22/2024
  • 37. Werner syndrome (Adult Progeria) sy synd ndro rom me e Werner syndrome is a hereditary condition associated with premature aging and an increased risk of cancer and other diseases. The signs of Werner syndrome usually develop in the teenage years. A person with Werner syndrome does not have the usual growth spurt typical of a teenager and is shorter on average. Signs of aging, including gray hair and hair loss as early as in 20s. Biochemistry for Medics-Lecture Notes 34 37
  • 38. Xeroderma pigmentosum (XP) • • • • • Xeroderma pigmentosum (XP) is an autosomal recessive genetic disease. The clinical syndrome includes marked sensitivity to sunlight (ultraviolet) with subsequent formation of multiple skin cancers and premature death. The risk of developing skin cancer is increased 1000- to 2000-fold. The inherited defect seems to involve the repair of damaged DNA, particularly thymine dimers. Cells cultured from patients with xeroderma pigmentosum exhibit low activity for the nucleotide excision-repair process. 38 2/22/2024
  • 39. Acknowledgement 39 • http://highered.mcgraw- hill.com/sites/0072556781/student_view0/ch apter11/animation_quiz_5.html • http://highered.mcgraw- hill.com/sites/dl/free/0072835125/126997/an imation34.html • Original script : Dr Namrata Chhabra, Biochemistry for medics • http://highered.mcgraw- hill.com/sites/dl/free/0072835125/126997/an imation33.html • Images courtesty: google 2/22/2024