Description
1) answers the questions in the groupwork document using the provided slides.2) After looking over the slides, provide a summary including:a. In your own words, describe the key ideas (~ 1 paragraph)b. What are some examples that illustrate these ideas?c. How do these ideas relate to what you already know?
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GROUPWORK 5
GROUP Number _____
Participating group members:
Molecular Biology of Cancer
2 Nov 2023
Provide as many examples as possible of proteins regulated by the following mechanisms. It might be useful to look
at the cast list for the play and consider which category or categories each protein fits into. Some proteins are in
more than one category. For some, we did not discuss the specific mechanism by which their activity is regulated (like
ATM, for instance). You can add those to the last category. You can also think about other proteins we discussed in
class but that weren’t part of the play to add to your lists. Try on your own to get 1-2 proteins listed in each category
and then, as a group, expand your lists to include as many as possible.
1. Protein is made and degraded unless needed
2. Protein is phosphorylated to activate
3. Protein is phosphorylated to inactivate
4. Protein only active when bound to a different protein (ie. protein functions as heterodimer or trimer)
5. Protein moves to (is recruited to) the plasma membrane by binding an “upstream” component of a signal
transduction pathway
6. Protein is inhibited by another protein bound to it
7. Protein is made in larger inactive form and then cleaved to activate
8. Protein is secreted from the cell
9. We didn’t learn about how this protein is activated:
EXAM 3 on November 7
Review Sessions (Anika, GTA)
Friday, Nov. 3
5pm– 7049 Haworth
Saturday, Nov. 4 5pm- zoom only
https://kansas.zoom.us/j/99308336674
Meeting ID: 933 0833 6674
Passcode: 817351
Lecture 20: Multi-Step Tumorigenesis, recap.
• How many steps to transform?
– Mouse is NOT equal to human
• Concept of non-mutagen contributing to cancer
– inflammation
Lect. 20: Maintenance of Genomic Integrity
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication
– Fixed by proofreading, MMR
• lost in Hereditary Nonpolyposis Colorectal Cancer
(HNPCC)
1b. dsDNA breaks during DNA replication or the result of
ionizing radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non Homologous End Joining (NHEJ)
Mechanics of tumor formation:
How many cells? How much time?
How many steps/mutations?
Question #4: Can tumorigenesis
be reconstructed in the lab? If
so…how many steps/mutations
does it take experimentally?
transformed cells
adenovir.
oncogenic
transformed cells
Cells are 3T3 rodent fibroblasts (immortal)
score Card
Steps/Mutations required for tumorigenesis:
•
Mouse 3T3 fibroblasts (immortal)
1
oncogenic
adenovir.
Cells are primary rodent cells
E1A inhibits Rb
score Card
Steps/Mutations required for tumorigenesis:
•
•
Mouse 3T3 fibroblasts (immortal)
1
Mouse primary fibroblasts (mortal)
2
Figure 11.24a The Biology of Cancer (© Garland Science 2007)
score Card
Steps/Mutations required for tumorigenesis:
•
•
•
Mouse 3T3 fibroblasts (immortal)
1
Mouse primary fibroblasts (mortal)
2
Whole animal (mouse)
>2
oncogenic
adenovir.
Cells are primary human cells
Viral Oncoproteins inhibit Ser/Thr
phosphatase, PP2A
Barski et al., Front. Cell. Infect. Microbiol (2021)
1
2
3
4
score Card
Steps/Mutations required for tumorigenesis:
•
•
•
•
Mouse 3T3 fibroblasts (immortal)
1
Mouse primary fibroblasts (mortal)
2
Whole animal (mouse)
>2
Human primary cells
4
score Card
Steps/Mutations required for tumorigenesis:
•
•
•
•
Mouse 3T3 fibroblasts (immortal)
1
Mouse primary fibroblasts (mortal)
2
Whole animal (mouse)
>2
Human primary cells
4
(5 pathways…but SV40 large T Ag= knocking out 2 TS proteins,
so really ~6)
(Deaths per 100,000 population)
Epidemiology/fancy math: 6 independent events,
each random with equal probability over time
Age at death from various epithelial cancers
Chronic inflammation can promote tumor progression
Figure 11.41 The Biology of Cancer (© Garland Science 2007)
Table 11.5 The Biology of Cancer (© Garland Science 2014)
(p21)
Biological attributes shared by
most cancers
1. ability to generate own mitogenic signals
2. to resist exogenous growth-inhibitory signals
3. to evade apoptosis
4. to proliferate without limits (i.e. undergo
immortalization)
5. acquisition of genomic instability
6. to acquire vasculature (i.e. undergo
angiogenesis
7. to invade and metastasize (in more advanced
cancers)
8. ability to evade elimination by immune system
Chapter 12
SHAPING AND
CHARACTERIZING THE
CANCER GENOME
“The capacity to blunder slightly is
the real marvel of DNA. Without
this special attribute, we would
still be anaerobic bacteria and
there would be no music.”
– Lewis Thomas, biologist, 1979
Copyright © 2023, W. W. Norton & Company, Inc.
Ways to get DNA mutations and how they are fixed
1. Errors in DNA Replication
a. mismatched bases or DNA polymerase “stutter” / microsatellite instability
b. dsDNA breaks during DNA replication (at replication fork)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
DNA Replication
Replication Fork
RNA primer
here as well
d (elongates DNA strand)
Figure 12.6 The Biology of Cancer (© Garland Science 2007)
Figure 12.4 The Biology of Cancer, 2023
d
Figure 12.6 (part 1 of 2) The Biology of Cancer (© Garland Science 2007)
Figure 12.4 The Biology of Cancer, 2023
Figure 12.6 (part 2 of 2) The Biology of Cancer (© Garland Science 2007)
Figure 12.4 The Biology of Cancer, 2023
Error rate of DNA replication:
•
DNA polymerase initial error rate
= 1 in ___________
Proof reading feature of DNA polymerase d (delta)
keeps mice from getting mutations → cancer
DNA pol d
w/o proof reading
Figure 12.7 The Biology of Cancer (© Garland Science 2007)
Tumors, skin
& lymphomas
Figure 12.5 The Biology of Cancer, 2023
Error rate of DNA replication:
•
DNA polymerase initial error rate
= 1 in ________
• 3’ → 5’ exonuclease fixes 99 of 100 errors
= 1 in _______
Hereditary nonpolyposis Colon Cancer
(HNPCC) Syndrome [Lynch]
• Characterized by multiple colon cancers at an early
age.
• Even though the name has nonpolyposis in it, people
with HNPCC will still develop a small number of polyps
as a precursor to colon cancer.
• Name is a bit of a misnomer for 2nd reason. HNPCC is
not a form of cancer, it is only a syndrome that puts
people at high risk for colon cancer.
• Mutations in mismatch repair genes (human Mut L
and S homologs) are related to this syndrome.
• People who have inherited this condition are also at
increased risk for a number of other types of cancers
including uterine, ovarian, endometrial, and stomach.
Mismatch repair (MMR) : MutS/MutL repair proteins
(in addition to DNA pol d & e)
LOOKS for
MutSa=MSH6
+ MSH2
MutLa=MLH1
+ PMS2
Figure 12.6 The Biology of Cancer, 2023
Error rate of DNA replication:
•
DNA polymerase initial error rate
= 1 in
• 3’ → 5’ exonuclease fixes 99 of 100 errors
= 1 in
• Mismatch Repair (MMR) fixes 99 of 100
TOTAL error rate= 1 in ______
Diploid genome = __________bp; ~ 6 mistakes per cell division
Ways to get DNA mutations and how they are fixed
1. Errors in DNA Replication [~ 6 per ‘S’ phase]
1a. mismatched bases or DNA polymerase “stutter” / microsatellite instability
• Fixed by proofreading, MMR
• lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
Replication Fork
RNA primer
here as well
dsDNA breaks
• ssDNA breaks at DNA
replication fork
• ionizing radiation (x-rays or
gamma rays)→ dsDNA
breaks
dsDNA breaks are ideally fixed by
Homology Directed Repair (HDR)
HDR
Repair Proteins:
BRCA1
BRCA2
RAD51
Figure 12.32 The Biology of Cancer (© Garland Science 2007)
Figure 12.30 The Biology of Cancer, 2023
Homology Directed Repair (HDR)
Figure 12.32 part 1 of 2 The Biology of Cancer (© Garland Science 2007)
Figure 12.30 The Biology of Cancer, 2023
C
Repair Proteins:
BRCA1
BRCA2
RAD51
Figure 12.32 part 2 of 2 The Biology of Cancer (© Garland Science 2007)
Figure 12.30 The Biology of Cancer, 2023
BRCA1/BRCA2 protein complex in HDR
Bind to single strand
DNA
Figure 12.31 The Biology of Cancer, 2023
BRCA1 and BRCA2
• BRCA 1 and BRCA2 organize repair of dsDNA breaks via
Homology Directed Repair (HDR)
• BRCA1 discovered by Mary Claire King lab (Berkeley, CA)
by analysis of inherited mutation in breast cancer patients.
• If you are a women inheriting a
mutation in one of these genes, 4565% chance of getting breast cancer
before the age of 70. (*different from
APC)
• Also involved in ovarian CA risk (esp.
BRCA1)
• 5-10% of all breast cancers have
mutations in either BRCA1 or
BRCA2 (*different from APC)
Mary Claire King
CHANCES OF DEVELOPING
BREAST CANCER BY AGE 70
CHANCES OF DEVELOPING
OVARIAN CANCER BY AGE 70
Estimated Cumulative Risks of Breast
and Ovarian Cancer in Mutation Carriers
JAMA. 2017;317(23):2402-2416
Inherited BRCA1 mutation
1 in 400 of
population has
inherited mutation
in BRCA1
BRCA Q: is radiation bad in screening
women with BRCA1/2 mutations?
•
•
•
•
•
“Some studies suggest these BRCA1 and BRCA2 cancers are more
sensitive, which would indicate better outcomes when treated with
radiation; however, others do not. The most recent studies indicate that
these women benefit from radiation to the same degree as those with
sporadic breast cancers.” – Junran Zhang, MD, PhD, Department of
Radiation Oncology, Case Western Reserve University School of Medicine,
Cleveland, Ohio
BRCA1/2 carriers need to be screened for breast cancer at an earlier
age and more frequently than other women.
While the radiation during mammography can increase the risk of
breast cancer over time, this increase is very small. -Br J Cancer. 93:5906, 2005
For BRCA1/2 carriers however, there’s some concern the radiation
exposure from screening mammography before age 30 may increase
breast cancer risk more than for other women.- BMJ. 345:e5660, 2012
This issue is under active study.
BRCA Q: what about men?
•
•
•
•
•
•
Men who have a BRCA2 mutation (BRCA2 carriers) have an increased
risk of breast cancer.
For example, the lifetime risk of breast cancer (up to age 80) is:
About 50-80 in 1,000 men with a BRCA2 mutation
Less than 1 in 1,000 men without a BRCA2 mutation (vs. 1 in 8 for
women)
Men who have a BRCA1/2 mutation have an increased risk of prostate
cancer.
The lifetime risk of prostate cancer (up to age 80) is:
10 percent for men in the general population
7-25 percent for men with a BRCA1 mutation
20-60 percent for men with a BRCA2 mutation
BRCA1/2 carriers may also have an increased risk of pancreatic cancer
and some second primary cancers (new cancers that develop after a first
breast cancer). -https://ww5.komen.org/
However, data are limited and these topics are still under study.
“Using available clinical data, we develop a Markov decision process model of a mutation carrier’s health states and corresponding transitions, including
age-dependent breast and ovarian cancer risk, distribution of each cancer subtype and stage, and mortality. We convert the problem to a linear program to
solve for the optimal surgery sequence that maximizes the carrier’s expected lifetime quality-adjusted life years (QALYs) under varying assumptions about
individual patient preferences on postsurgery quality of life, fertility considerations, advances in cancer screening or treatment, and others. Baseline results
demonstrate that a QALY-maximizing sequence recommends BM between ages 30 and 60 and BSO after age 40. Surgeries are recommended later for
BRCA2 mutation carriers, given their lower risk for both cancers compared to BRCA1 mutation carriers. We derive structural properties from the model and
show that when a carrier has already undergone one surgery, there exists an optimal control limit beyond which performing the other surgery is always
QALY maximizing.”
Homology Directed Repair (HDR)
HDR
Repair Proteins:
BRCA1
BRCA2
RAD51
Figure 12.32 The Biology of Cancer (© Garland Science 2007)
Figure 12.30 The Biology of Cancer, 2023
Ways to get DNA mutations and how they are fixed
1. Errors in DNA Replication [~ 6 per ‘S’ phase]
1a. mismatched bases or DNA polymerase “stutter” / microsatellite instability
• Fixed by proofreading, MMR
•
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
Nonhomologous End Joining (NHEJ)
Figure 12.33 The Biology of Cancer (© Garland Science 2007)
Figure 12.32 The Biology of Cancer, 2023
NHEJ could
contribute to
massive
chromosome
rearrangement
Figure 12.35B The Biology of Cancer, 2023
NHEJ plays critical role in
breakage fusion bridge
(BFB) cycle that contributes
to chromosome fusion.
NHEJ could make massive
chromosome rearrangement
as shown left.
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication [~ 6 per ‘S’ phase]
• Fixed by proofreading, MMR
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
dsDNA breaks
• ssDNA breaks during DNA
replication
• ionizing radiation (x-rays or
gamma rays)→ dsDNA
breaks
Pyrimidine dimer=bulky damage
UV
T=T
C=T
C=C
Figure 12.12a The Biology of Cancer (© Garland Science 2014)
Nucleotide Excision Repair (NER) in humans
XPC and XPE recognize damage,
XPC
binding leads to recruit helicases
XPB + XPD → regional melting
XPE
XPF
XPG
XPB
endonucleases XPF and XPG
nick one strand, excising 24-32
nt piece
XPD
e,d
UV-induced Thymine or Cytosine dimer damage is
repaired by NER: Study from UV hyper sensitive
patients = XP (Xeroderma Pigmentosum)
XP (Xeroderma Pigmentosum) patients have
higher risk of skin cancer.
Skin cancer rate of XP patients
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication [~ 6 per ‘S’ phase]
• Fixed by proofreading, MMR
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
• Physical Mutagen
– X-ray –> ss and dsDNA breaks (HDR or NHEJ)
– UV irradiation →pyrimidine dimers
• NER
• Xeroderma Pigmentosum and XP variant (XPV)
EXAM 3 on November 7
Review Sessions (Anika, GTA)
Thursday, Nov. 2 5pm– 7049 Haworth
Saturday, Nov. 4 5pm- zoom only
https://kansas.zoom.us/j/99308336674
Meeting ID: 933 0833 6674
Passcode: 817351
Lecture 21: Maintenance of Genomic Integrity
Ways to get DNA mutations and how they are fixed, cont.
1. dsDNA breaks [e.g.During DNA replication ssDNA breaks, or
resulting from X-ray exposure]
•
•
HDR
NHEJ
2. Endogenous biochemical Processes (oxidation, depurination,
methylation, deamination)
3. Attack by exogenous mutagens (more occasional)
Physical Mutagen
X-ray –> ss and dsDNA breaks (see HDR and NHEJ from 1.)
UV irradiation pyrimidine dimers
NER=Nucleotide Excision Repair
Xeroderma Pigmentosum and XP variant (XPV)
Chemical Mutagen
• Modified base can be fixed by directly undoing
• Base Excision Repair BER
BRCA Q: is radiation bad in screening
women with BRCA1/2 mutations?
•
•
•
•
•
“Some studies suggest these BRCA1 and BRCA2 cancers are more
sensitive, which would indicate better outcomes when treated with
radiation; however, others do not. The most recent studies indicate that
these women benefit from radiation to the same degree as those with
sporadic breast cancers.” – Junran Zhang, MD, PhD, Department of
Radiation Oncology, Case Western Reserve University School of Medicine,
Cleveland, Ohio
BRCA1/2 carriers need to be screened for breast cancer at an earlier
age and more frequently than other women.
While the radiation during mammography can increase the risk of
breast cancer over time, this increase is very small. -Br J Cancer. 93:5906, 2005
For BRCA1/2 carriers however, there’s some concern the radiation
exposure from screening mammography before age 30 may increase
breast cancer risk more than for other women.- BMJ. 345:e5660, 2012
This issue is under active study.
BRCA Q: what about men?
•
•
•
•
•
•
Men who have a BRCA2 mutation (BRCA2 carriers) have an increased
risk of breast cancer.
For example, the lifetime risk of breast cancer (up to age 80) is:
About 50-80 in 1,000 men with a BRCA2 mutation
Less than 1 in 1,000 men without a BRCA2 mutation (vs. 1 in 8 for
women)
Men who have a BRCA1/2 mutation have an increased risk of prostate
cancer.
The lifetime risk of prostate cancer (up to age 80) is:
10 percent for men in the general population
7-25 percent for men with a BRCA1 mutation
20-60 percent for men with a BRCA2 mutation
BRCA1/2 carriers may also have an increased risk of pancreatic cancer
and some second primary cancers (new cancers that develop after a first
breast cancer). -https://ww5.komen.org/
However, data are limited and these topics are still under study.
Inherited BRCA1 mutation
1 in 400 of
population has
inherited mutation
in BRCA1
“Using available clinical data, we develop a Markov decision process model of a mutation carrier’s health states and corresponding transitions, including
age-dependent breast and ovarian cancer risk, distribution of each cancer subtype and stage, and mortality. We convert the problem to a linear program to
solve for the optimal surgery sequence that maximizes the carrier’s expected lifetime quality-adjusted life years (QALYs) under varying assumptions about
individual patient preferences on postsurgery quality of life, fertility considerations, advances in cancer screening or treatment, and others. Baseline results
demonstrate that a QALY-maximizing sequence recommends BM between ages 30 and 60 and BSO after age 40. Surgeries are recommended later for
BRCA2 mutation carriers, given their lower risk for both cancers compared to BRCA1 mutation carriers. We derive structural properties from the model and
show that when a carrier has already undergone one surgery, there exists an optimal control limit beyond which performing the other surgery is always
QALY maximizing.”
BRCA1/BRCA2 protein complex in HDR
Bind to single strand
DNA
Figure 12.31 The Biology of Cancer, 2023
Homology Directed Repair (HDR)
HDR
Repair Proteins:
BRCA1
BRCA2
RAD51
Figure 12.32 The Biology of Cancer (© Garland Science 2007)
Figure 12.30 The Biology of Cancer, 2023
Ways to get DNA mutations and how they are fixed
1. Errors in DNA Replication [~ 6 per ‘S’ phase]
1a. mismatched bases or DNA polymerase “stutter” / microsatellite instability
• Fixed by proofreading, MMR
•
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
Nonhomologous End Joining (NHEJ)
Figure 12.33 The Biology of Cancer (© Garland Science 2007)
Figure 12.32 The Biology of Cancer, 2023
NHEJ could
contribute to massive
chromosome
rearrangement
NHEJ plays critical role in
breakage fusion bridge (BFB)
cycle that contributes to
chromosome fusion.
NHEJ could make massive
chromosome rearrangement as
shown left.
Also key for V, D, J segment
recombination in immunoglobulin
gene segments to generate Abs
Figure 12.35B The Biology of Cancer, 2023
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication [~ 6 per ‘S’ phase]
• Fixed by proofreading, MMR
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
• Physical Mutagen
– X-ray –> ss and dsDNA breaks (HDR or NHEJ)
dsDNA breaks
• ssDNA breaks during DNA
replication
• ionizing radiation (x-rays or
gamma rays) dsDNA
breaks
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication [~ 6 per ‘S’ phase]
• Fixed by proofreading, MMR
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
• Physical Mutagen
– X-ray –> ss and dsDNA breaks (HDR or NHEJ)
– UV irradiation pyrimidine dimers
Pyrimidine dimer=bulky damage
UV
T=T
C=T
C=C
Figure 12.12a The Biology of Cancer (© Garland Science 2014)
Nucleotide Excision Repair (NER) in humans
XPC and XPE recognize damage,
XPC
binding leads to recruit helicases
XPB + XPD regional melting
XPE
XPF
XPG
XPB
endonucleases XPF and XPG
nick one strand, excising 24-32
nt piece
XPD
ε,δ
UV-induced Thymine or Cytosine dimer damage is
repaired by NER: Study from UV hyper sensitive
patients = XP (Xeroderma Pigmentosum)
Figure 12.23 The Biology of Cancer, 2023
XP (Xeroderma Pigmentosum) patients have
higher risk of skin cancer.
Skin cancer rate of XP patients
Error Free bypass: During DNA synthesis: Bypass
of damaged region by DNA polymerase η
η
thymine
dimer
DNA pol η (eta), also known as XPV, automatically put AA in new strand
across from pyrimidine dimer region
Error-prone bypass : Bypass of damaged
region by DNA polymerase ζ
DNA pol ζ (zeta), puts random nucleotide in new strand across from
pyrimidine dimer region
Figure 12.21 The Biology of Cancer, 2023
ζ
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication [~ 6 per ‘S’ phase]
• Fixed by proofreading, MMR
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
• Physical Mutagen
– X-ray –> ss and dsDNA breaks (HDR or NHEJ)
– UV irradiation pyrimidine dimers
• NER
• Xeroderma Pigmentosum and XP variant (XPV)
• Chemical Mutagen
• Chemical carcinogens like BaP that result in bulky, helix-distorting alterations
(NER)
Figure 12.13 The Biology of Cancer, 2023
DNA adduct
-formed after reaction of carcinogen with a DNA base
Figure 12.14 The Biology of Cancer, 2023
Ways to get DNA mutations and how they are fixed
1a. Errors in DNA Replication [~ 6 per ‘S’ phase]
• Fixed by proofreading, MMR
lost in Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
1b. dsDNA breaks during DNA replication [~10 per ‘S’ phase] or the result of ionizing
radiation (X-ray, gamma ray)
– Homology directed repair (HDR)
• BRCA1 and BRCA2
– Non homologous End Joining (NHEJ)
2. Endogenous biochemical Processes (oxidation, depurination, methylation,
deamination)
3. Attack by exogenous mutagens (more occasional)
• Physical Mutagen
– X-ray –> ss and dsDNA breaks (HDR or NHEJ)
– UV irradiation pyrimidine dimers
• NER
• Xeroderma Pigmentosum and XP variant (XPV)
• Chemical Mutagen
• Chemical carcinogens like BaP that result in bulky, helix-distorting alterations
(NER)
• Modified base can be fixed by directly reversing modification e.g. MGMT
• Base Excision Repair BER
The problem with alkylation damage
Weaver, Molecular Biology (2005)
Some alkylation damage can be directly
repaired if MGMT is available
MGMT: O6-methylguanine-DNA methyltransferase
Figure 12.19The Biology of Cancer, 2023
Modification like
alkylation or
deamination
Base Excision Repair (BER)
For repair of modified DNA base
(e.g. alkylation or deamination)
APE
PARP
1. DNA glycosylase cleaves glycosyl
bond to remove base.
2. Apurinic/apyrimidinic (AP)
endonuclease (APE) cleaves
backbone, removes sugar phosphate.
3. PARP helps recruit other proteins to
ssDNA break
4 DNA Pol replaces the nucleotide,
sealed by ligase.
Figure 12.20 The Biology of Cancer, 2023
(Cell cycle arrest)
(Cell death)
and η
DNA Repair Pathways
Replication errors
A
G
X-Rays, ssDNA
breaks during ‘S’
C
T
A-G mismatch
C-T mismatch
“microsattelite”
Mismatch Repair
UV light
T
double strand break
Exogenous
chemicals
T
chemical mutagens
(e.g. alkylating agents)
endogenous biochemical
processes (e.g. oxidation)
G
DNA adducts
pyrimidine dimers
modified base
e.g. O6-ethylguanine
Homology Directed Repair Nucleotide-Excision Repair
or Nonhomologous End Joining
(MMR) (HDR or NHEJ) (NER)
Base-Excision Repair
(BER)
#
1
Members
Debbie-W , Cody-A , Anasuya-S , Shannon-A ,Tristan-C
Seats
27, 25, 24, 10, 8
2
Mueez-A, Riley-C , Kade-C , Eva-B , Emily-M, Lexy-F
5, 4, 22, 21, 20, 19
3
Shira-E , Kilee-H , Allison-S, Brie-S, Emma-H, Chloe-H
18, 17, 16, 15, 3, 2
4
Shelby-C, Courtney-W , Kael-M , Allison-C, Gabbie-Daw, Ryan-L
14, 13, 12, 11, 0, 0
5
Juan-M , Laiba-A, Lilly-C , Abu-Baker-A , Lauren-G, Sophie-H
97, 96, 95, 94, 75, 73
6
Bakthi-N , Nhu-B , Quincy-M , Mia-R , Jonathan-M
68, 67, 66, 46, 44
7
Anna-F , Megan-B , Brandon-D , Kamar-C, Austin-B
64 63, 62, 42, 40
8
Francesca-L, Jenna-S , Sophia-T , Abhirup-M , Cameron-D
99, 98, 90, 89, 87
9
Abdallah-B , Samantha-F , Ethan-G , CJ-G , Erin-R
83, 82, 81, 60, 59
10 Rana-A , Cole-C , Eleazar-A, Lauren-M, Parijat-M
58, 57, 56, 36, 35
11 Riya-P , Cassidy-B , Reagan-R , Braedon-M , Cameron-K
54, 53, 52, 34, 32
12 Adrienne-J, Samantha-Y , Ebru-A, Gabrielle-Dex, Arsalan-Z
93, 92, 91, 70, 69
1. Protein is made and degraded unless needed
2. Protein is phosphorylated to activate
3. Protein is phosphorylated to inactivate
4. Protein only active when bound to a different protein (ie. protein functions as
heterodimer or heterotrimer)
5. Protein moves to (is recruited to) the plasma membrane by binding an “upstream”
component of a signal transduction pathway
6. Protein is inhibited by another protein bound to it
7. Protein is made in larger inactive form and then cleaved to activate
8. Protein is secreted from the cell
9. We didn’t learn about how this protein is activated:
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