DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage,...
Transcript of DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage,...
![Page 1: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/1.jpg)
DNA damage, repair and diseasesProf. Tsai-Kun (TK) Li,
Dept. & Grad. Inst. of Microbiology,
National Taiwan University College of Medicine
88287/88294; [email protected]
DNA
synthesis
Growth
Growth
Parental
cell
Offspring
cells
Mitosis
Cell division
G0: somatic cells
Genome integrity
![Page 2: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/2.jpg)
2015: The Year of Repair (Molecular Cell vol.60)
Dept. Biochemistry and
Molecular Biology
National Taiwan University
College of Medicine
Prof. Jing-Jer Lin
Dept. Clinical Laboratory
Sciences and Medical
Biotechnology
National Taiwan University
College of Medicine
Prof. Jing-Jer Lin
![Page 3: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/3.jpg)
DNA damage response and signaling
Cell cycle Transcription DNA repair Cell death
checkpoint control program activation * direct reversal * apoptosis
* NER * necrosis
* MMR
* HR .… etc. …. etc.
Genome instability diseases & death
Endogenous Exogenous
3’
5’
Cellular replication Ionization Chemical UV light metabolism errors radiation damage exposure
Mitoticfailure
![Page 4: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/4.jpg)
Local structure alteration created by DNA damage--- potential sources/substrates for detection
![Page 5: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/5.jpg)
DNA damage, corresponding signaling & responses
Sources
Activation
Processing
Impacts
DSBSSB
Protein-
capped SSBBulky
adduct
MismatchChromatin
alteration
Telomere
dysfunctionRadio- and
chemotherapy
Alkylating
agentsReplication
errors
X-raysAID
UV light
Topoisomerase
3’
5’
U
GT^T
CH3
G8oxo
Oxidants
Sensors
Transducers
Effectors
DNA repair
Transcription
SOS
Apoptosis
Cell cycle
transitionsSTOP
Hiden
DSB
recognition
transduction
amplification
exo or endo
![Page 6: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/6.jpg)
Types of DNA damage and corresponding repairs
Causes
Damages
Repair
pathways
DSBSSB
Protein-
capped SSBBulky
adduct
MismatchChromatin
alteration
Telomere
dysfunctionRadio- and
chemotherapy
Alkylating
agentsReplication
errors
X-raysAID
UV light
Topoisomerase
3’
5’
U
GT^T
CH3
G8oxo
Oxidants
MMR
BERHR
NHEJHR
NHEJ
Ub/
proteasome
SSA
BER
HR
NHEJ
NER
BER
removal
Chromatin
remodeling ?
Reversal ?
HR
NHEJ
Hiden
DSB
![Page 7: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/7.jpg)
In prokaryotic cells
![Page 8: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/8.jpg)
Bacterial DNA damage responses --- transcription activation and gene expression
SOS response Adaptive response Oxidative response
www.scielo.br/cgi-bin/wxis.exe/
?IsisScript=Sc...DNA repair and mutagenesis
(1995) Friedberg EC et al
SOS genes: uvrA/B/D
recN/F
ftsK, sulA
![Page 9: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/9.jpg)
The network of SOS response to DNA damage
sensing
checkpoint
checkpoint
![Page 10: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/10.jpg)
Recombination repair proteins in bacteria
![Page 11: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/11.jpg)
Base excision repair (BER)
![Page 12: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/12.jpg)
Nucleotide excision repair (NER)
![Page 13: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/13.jpg)
Mismatch repair (MMR)
![Page 14: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/14.jpg)
www.mun.ca/.../4103/topics/mutagenesis.htmlModified from
G TO6 O4
meme
The adaptive response to alkylating agents
G T
NTD CTD
meme
me
methyl
trasnfer
![Page 15: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/15.jpg)
Induction of the OxyR regulon
![Page 16: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/16.jpg)
In eukaryotic cells
![Page 17: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/17.jpg)
Local structure alteration created by DNA damage:
--- sources/substrates for damage detection
![Page 18: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/18.jpg)
Local chromatin alteration created by DNA damage:--- detection and repair accessibility
Isoforms
& tails
![Page 19: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/19.jpg)
Histone modification after DNA damage:--- accessibility & signaling for downstream events
Cancer Science 97 (10), 984-989
H3 K56 acetylation H4K methylation
H2A & H2AX
ubiquitination
Enhanced P-P interactions
--- specificity
![Page 20: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/20.jpg)
The general outline of DNA damage response --
- signal-transduction pathway in eukaryotic cells
![Page 21: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/21.jpg)
Organization of DNA damage
response/pathway in mammalian cells
DNA-PK
![Page 22: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/22.jpg)
Conserved recruitment of ATM, ATR and
DNA-PKcs to sites of DNA damage
ATMATR
DNA-PKcs
![Page 23: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/23.jpg)
Oncogene (2005) 24, 2871–2876
ssDNA/RPA acts as a ligand for activation of
the ATR-CHK1 checkpoint pathway
ssDNA and RPA act
as an activation ligand
recruitment of
911 complex/ ATRIP
Claspin ?
focus formation:
cytological marker
5’ 3’ resection
Key kinase
molecule
for DDR
![Page 24: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/24.jpg)
Formation of DNA damage foci --- an important cytological DNA damage marker ---
untreated
DNA
damage
signaling
recombination repair*
![Page 25: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/25.jpg)
Watching the DNA repair ensemble dance
Cell. 2004 Sep 17;118(6):666-8
kinase
cascade
![Page 26: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/26.jpg)
Cell. 2004 Sep 17;118(6):699-713
Model for recruitment of checkpoint and recombination proteins to a DSB
--- Choreography of checkpoint activation and DNA repair ---
![Page 27: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/27.jpg)
Driving forces:--- phosphopeptide-binding molecules
FHA domain BRCT domainRad53 - pThrXXAsp BRCA1 - gH2AX (pSXXF)
pS/TQ
![Page 28: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/28.jpg)
DNA damage: --- ubiquitin marks the damaging spot on chromatin
Nature Structural & Molecular Biology 15, 20 - 22 (2008)
![Page 29: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/29.jpg)
Turning off DNA damage checkpoints
1. Reversal of activating phosphorylations: Protein phosphatases
could act to reverse the DNA damage induced phosphorylations.N.R. den Elzen, M.J. O’Connell, EMBO J. 23 (4) (2004) 908–918.
2. Proteolysis of activated checkpoint proteins: Ubiquitin-dependent
proteolysis of activated checkpoint proteins ---
phosphorylation/activation acts as a mark for ubiquitination
Y.W. Zhang, et al., Mol. Cell 19 (5) (2005) 607–18.
I. Mamely, et al., Curr. Biol. 16 (19) (2006) 1950–5.
3. Checkpoint antagonists: Independent pathways could antagonize
the cell cycle arrest induced by checkpoint activation.T.R. Coleman, Z. Tang, W.G. Dunphy, Cell 72 (1993) 919–29.
4. De-ubiquitination (DUB): USP13 & Brcc36.F. Nicassio et al. Curr. Biol. 17 (2007) 1972-7.
Nature Structural & Molecular Biology 15 (2008) 20-2.
![Page 30: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/30.jpg)
Modification of the ubiquitin signal:not yet finished off
Nature Structural & Molecular Biology 15, 20 - 22 (2008)
USP28
DeUb EnzymeUSP28 in Control of the DNA-
Damage Response, Cell 126, 529–542, 2006
TAP-53BP1 IP USP28
![Page 31: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/31.jpg)
Activation of repair pathway --- ssDNA and RPA act as a substrate for HR ---
Oncogene (2005) 24, 2871–2876
recruitment of
BRCA2/ DSS1
![Page 32: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/32.jpg)
Homologous recombination (HR)Non-homologous
end joining (NHEJ)
Double strand break (DSB) repair
![Page 33: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/33.jpg)
Mismatch Repair (MMR)
![Page 34: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/34.jpg)
PLoS Biology June 2006 | Volume 4 | Issue 6 | e203
Nucleotide excision repair (NER)
ub
![Page 35: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/35.jpg)
PLoS Biology June 2006 | Volume 4 | Issue 6 | e203
Transcription-coupled repair (TCR)
![Page 36: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/36.jpg)
TFIIH Is a multi-functional protein complex--- Linking transcription and repair ---
PLoS Biology June 2006 | Volume 4 | Issue 6 | e203
![Page 37: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/37.jpg)
Poly ADP-ribose polymerase-1 (PARP-1) in
transcription and repair
![Page 38: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/38.jpg)
DNA damage, genome instability, cancer
development and aging
Colorectal cancer as an example
![Page 39: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/39.jpg)
Parallel pathways of tumorigenesis
--- Hallmarks of cancer/where we stand in the fight against cancer
![Page 40: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/40.jpg)
Emerging hallmarks & enabling characteristics
An evolving hallmark
Just accelerating?
Cancer arises from a series of genetic alterations that
promote resistance to apoptosis, self-sufficiency in
growth, cellular immortalization and escape from cell-
cycle-exit. Hanahan and Weinberg, Cell (2011) 144:646-74
Microenvironment
![Page 41: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/41.jpg)
Genome instability and Cancer development
On and off Mis-regulation Genome instability Cancer
development
Cancer Types Inter-tumor heterogeneity Intra-tumor
heterogeneity
Many oncogenic mutations confer a cell-autonomous fitness
+ microenvironment (non-cell-autonomous driving of growth) ???
Genome instability Mutations Dysfunctions Diseases & Death
Endogenous Exogenous
3’
5’
Cellular replication Ionization Chemical UV light metabolism errors radiation damage exposure
Cell cycle Transcription DNA repair Cell death checkpoint control program activation * direct reversal * apoptosis
* NER * necrosis
Mitotic failure
![Page 42: DNA damage, repair and diseases - 臺大數位知識典藏kan.ntu.edu.tw/ntu/194/67.pdfDNA damage, repair and diseases Prof. Tsai-Kun (TK) Li, Dept. & Grad. Inst. of Microbiology,](https://reader031.fdocuments.net/reader031/viewer/2022030720/5b053ea87f8b9abf568b64ee/html5/thumbnails/42.jpg)