Caspase-activated DNase

Last updated
DFFB
Protein DFFB PDB 1ibx.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DFFB , DNA fragmentation factor, 40kDa, beta polypeptide (caspase-activated DNase), CAD, CPAN, DFF-40, DFF2, DFF40, DNA fragmentation factor subunit beta
External IDs OMIM: 601883; MGI: 1196287; HomoloGene: 3241; GeneCards: DFFB; OMA:DFFB - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1677

13368

Ensembl

ENSG00000169598

ENSMUSG00000029027

UniProt

O76075

O54788

RefSeq (mRNA)

NM_007859

RefSeq (protein)

NP_001269598
NP_001307061
NP_001307065
NP_004393

NP_031885

Location (UCSC) Chr 1: 3.86 – 3.89 Mb Chr 4: 154.05 – 154.06 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
DNA fragmentation factor 40 kDa
PDB 1v0d EBI.jpg
Crystal structure of caspase-activated DNAse (CAD)
Identifiers
SymbolDFF40
Pfam PF09230
InterPro IPR015311
SCOP2 1v0d / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Caspase-activated DNase (CAD) or DNA fragmentation factor subunit beta is a protein that in humans is encoded by the DFFB gene. [5] [6] [7] It breaks up the DNA during apoptosis and promotes cell differentiation. It is usually an inactive monomer inhibited by ICAD. This is cleaved before dimerization.

Contents

Function

Apoptosis is a cell self-destruct process that removes toxic and/or useless cells during mammalian development and other life processes. The apoptotic process is accompanied by shrinkage and fragmentation of the cells and nuclei and degradation of the chromosomal DNA into nucleosomal units. DNA fragmentation factor (DFF) is a heterodimeric protein of 40-kD (DFFB) and 45-kD (DFFA) subunits. DFFA is the substrate for caspase-3 and triggers DNA fragmentation during apoptosis. DFF becomes activated when DFFA is cleaved by caspase-3. The cleaved fragments of DFFA dissociate from DFFB, the active component of DFF. DFFB has been found to trigger both DNA fragmentation and chromatin condensation during apoptosis. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [7]

CAD and ICAD forms CAD and ICAD forms.png
CAD and ICAD forms

Despite this gene being present in every cell, this protein is only expressed in different tissues and cell variety such as pancreas, heart, colon, leukocytes, prostate, ovary, placenta, kidney, spleen and thymus. [8]

It is also known as caspase activated nuclease (CPAN), dna fragmentation factor 40 (DFF-40), DFF2 and DFFB. Besides, there are other nomenclatures as a result of combining the previous ones. [8] [9] [10] [11]

Structure

This heterodimer is an endonuclease [9] [12] [13] with a high content of cysteine residues. [11] It remains inactive in growing cells while it is associated with its inhibitor (ICAD, DNA fragmentation factor 45 kDa subunit, DFFA or DFF45) resulting into a complex ICAD-CAD. [8] [9] [11] [12] [14] [15] [16] [17] Their dissociation allows DFF40 to oligomerize to form a large functional complex which is by itself an active DNase. [11] [12] [15] [16] [17]

DFF40 subunit or CAD

It weighs 40 kDa. Moreover, it contains three domains making up a CAD monomer: C1 or N-terminal CAD; C2 which conform three separate α chains and, at last, C3 which is the largest and functionally the most important. What is more, combining C3’s amino acids leads to 5 α helices, 4 β lamina and a loop at the catalytic C-terminal which interact with each other. Therefore, a cavity (active site) where DNA can fit is produced, even though there is another binding region responsible for stable DNA complex during its fragmentation. [8] [14] [18]

DFF45 subunit or ICAD

DFFA is encoded by an alternatively encrypted mRNAs originating two distinct forms: short (ICAD-S) and long (ICAD-L), which act like a specific chaperone ensuring the correct CAD's folding [10] [11] [17] Besides, it contains two aspartic acid residues (Asp117 and Asp224) where CAD is identified and, consequently, it stays bounded until Caspase-3 splits this union. [10] [14]

Activation process

Per usual in non-apoptotic growing cells caspase activated dnase is held in check inactivated in the cytoplasm thanks to the association with its inhibitor, inhibitor of caspase-activated DNase (ICAD) also known as DNA fragmentation factor 45 kDa (DFF45).

ICAD is encoded by alternatively spliced mRNAs which generate long (ICAD-L) and short (ICAD-S) forms of ICAD. Therefore, ICAD has a double function; it acts as a CAD inhibitor and also as a chaperone for CAD synthesis assisting the correct assembly of the protein. [19]

ICAD has two caspase recognition sites at Asp117 and Asp224. CAD release from ICAD inhibition is achieved by cleavage of ICAD at these Asp residues by the caspase-3. [20]

Caspase-3 is activated in the apoptotic cell. [9] Caspase-3 activation is a cell requirement during early stages of the skeletal myoblast differentiation. Its catalytic site involves sulfohydryl group of Cys-285 and the imidazole ring of its His-237. The caspase-3 His-237 stabilizes the target Aspartate causing the break of the association of ICAD and CAD leaving the endonuclease CAD active allowing it to degrade chromosomal DNA.

Once the inhibitor is released and in order to properly function, two CAD monomers need to come together to form a functional dimer that has vertical symmetry.

Interactions

DFFB has been shown to interact with DFFA. [21] [22]

Cell differentiation

Caspase 3 is responsible for cellular differentiation, although it is unclear how this kind of protein can promote the cell apoptosis. Caspase signals resulting from the activation of nuclease CAD indicate that the cell differentiation is due to a CAD modification in chromatin structure.

CAD leads to the initiation of the DNA strand breakage, which occurs during terminal differentiation of some cell, such as skeletal muscle cell. Targeting of p21 promoter is responsible for inducing cell differentiation, which is promoted by modifying the DNA nuclear microenvironment. [23]

The cell diversity is originated by cell differentiation, which has been attributed to the activation of specific transcription factors. It also depends on the activity of a protein or a common signal. The factor that seems to induce more cell differentiation is caspase-3 protease. [24] This was identified as the penultimate stage of apoptosis pathways cell.

Some studies have shown that this differentiation is due to many CAD kinase substrates. Referring to the example of skeletal cells, their differentiation is associated to cleavage of the kinase MST1. [25]

Moreover, it has been seen that CAD participates in the formation of genome whose DNA breaks during early stages of the cell differentiation. Besides, Caspase 3 induces DNA breaks in the promoter of the factor p21 and this strand breakup is related to p21 gene expression.

Cell apoptotic death

The protein caspase DNase is an endonuclease involved in the cell apoptotic process that facilitates the DNA breakup. [26] Cell apoptotic death is a process executed by cysteine proteases [27] that allows the animals to keep their homeostasis, also regulated by other mechanisms such as the growth and cell differentiation. This biological response is characterized by the chromosomal DNA’s degradation in tiny fragments within the nucleus of the cell. [28] After many investigations and research, it was possible to ensure that Caspase-activated DNase is the main responsible of this destruction due to a long list of stimuli.

One of the experiments carried out by the investigators in order to prove that theory was based on the introduction of mutated form of this protein inside both TF-1 human cells and Jurkat cells, which had already reacted to the usual (not mutated) form of the endonuclease and they had dead of apoptosis. As a result, these cells died taking into account this genetic modification but they did not show DNA breakup. This was the key evidence to prove that the CAD form is implicated in this part of the process because without its contribution the fragmentation did not take place. [29]

Later, it was found that the way how this protein induces the DNA breakup is explained by its forms CAD and ICAD, which facilitate both the entry and exit in the nucleus of the cell. [28]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

DNA fragmentation is the separation or breaking of DNA strands into pieces. It can be done intentionally by laboratory personnel or by cells, or can occur spontaneously. Spontaneous or accidental DNA fragmentation is fragmentation that gradually accumulates in a cell. It can be measured by e.g. the Comet assay or by the TUNEL assay.

<span class="mw-page-title-main">DNA laddering</span>

DNA laddering is a feature that can be observed when DNA fragments, resulting from Apoptosis DNA fragmentation are visualized after separation by gel electrophoresis the first described in 1980 by Andrew Wyllie at the University Edinburgh medical school DNA fragments can also be delected in cells that underwent necrosis, when theses DNA fragments after separation are subjected to gel electrophoresis which in the results in a characteristic ladder pattern,

<span class="mw-page-title-main">Apoptosis-inducing factor</span> Protein family

Apoptosis inducing factor is involved in initiating a caspase-independent pathway of apoptosis by causing DNA fragmentation and chromatin condensation. Apoptosis inducing factor is a flavoprotein. It also acts as an NADH oxidase. Another AIF function is to regulate the permeability of the mitochondrial membrane upon apoptosis. Normally it is found behind the outer membrane of the mitochondrion and is therefore secluded from the nucleus. However, when the mitochondrion is damaged, it moves to the cytosol and to the nucleus. Inactivation of AIF leads to resistance of embryonic stem cells to death following the withdrawal of growth factors indicating that it is involved in apoptosis.

<span class="mw-page-title-main">FADD</span> Human protein and coding gene

FAS-associated death domain protein, also called MORT1, is encoded by the FADD gene on the 11q13.3 region of chromosome 11 in humans.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Caspase 8</span> Protein found in humans

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

Fragmentation describes the process of splitting into several pieces or fragments. In cell biology, fragmentation is useful for a cell during both DNA cloning and apoptosis. DNA cloning is important in asexual reproduction or creation of identical DNA molecules, and can be performed spontaneously by the cell or intentionally by laboratory researchers. Apoptosis is the programmed destruction of cells, and the DNA molecules within them, and is a highly regulated process. These two ways in which fragmentation is used in cellular processes describe normal cellular functions and common laboratory procedures performed with cells. However, problems within a cell can sometimes cause fragmentation that results in irregularities such as red blood cell fragmentation and sperm cell DNA fragmentation.

<span class="mw-page-title-main">Caspase 3</span> Protein found in humans

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">PAK2</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.

<span class="mw-page-title-main">Caspase 10</span> Enzyme found in humans

Caspase-10 is an enzyme that, in humans, is encoded by the CASP10 gene.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">APAF1</span> Mammalian protein found in Homo sapiens

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.

<span class="mw-page-title-main">DFFA</span> Protein-coding gene in the species Homo sapiens

DNA fragmentation factor subunit alpha (DFFA), also known as Inhibitor of caspase-activated DNase (ICAD), is a protein that in humans is encoded by the DFFA gene.

<span class="mw-page-title-main">Serine protease HTRA2, mitochondrial</span> Enzyme found in humans

Serine protease HTRA2, mitochondrial is an enzyme that in humans is encoded by the HTRA2 gene. This protein is involved in caspase-dependent apoptosis and in Parkinson's disease.

<span class="mw-page-title-main">ENDOG</span> Protein-coding gene in the species Homo sapiens

Endonuclease G, mitochondrial is an enzyme that in humans is encoded by the ENDOG gene. This protein primarily participates in caspase-independent apoptosis via DNA degradation when translocating from the mitochondrion to nucleus under oxidative stress. As a result, EndoG has been implicated in cancer, aging, and neurodegenerative diseases such as Parkinson's disease (PD). Regulation of its expression levels thus holds potential to treat or ameliorate those conditions.

<span class="mw-page-title-main">Apoptotic DNA fragmentation</span> Cleavage of DNA into tiny pieces during apoptosis

Apoptotic DNA fragmentation is a key feature of apoptosis, a type of programmed cell death. Apoptosis is characterized by the activation of endogenous endonucleases, particularly the caspase-3 activated DNase (CAD), with subsequent cleavage of nuclear DNA into internucleosomal fragments of roughly 180 base pairs (bp) and multiples thereof (360, 540 etc.). The apoptotic DNA fragmentation is being used as a marker of apoptosis and for identification of apoptotic cells either via the DNA laddering assay, the TUNEL assay, or the by detection of cells with fractional DNA content ("sub G1 cells") on DNA content frequency histograms e.g. as in the Nicoletti assay.

Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the endoplasmic reticulum and golgi apparatus, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. In stage two, the reversibility threshold for the cell is passed and the cell becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response.

<span class="mw-page-title-main">Early 35 kDa protein</span> Anti-apoptotic viral protein

The Early 35 kDa protein, or P35 in short, is a baculoviral protein that inhibits apoptosis in the cells infected by the virus. Although baculoviruses infect only invertebrates in nature, ectopic expression of P35 in vertebrate animals and cells also results in inhibition of apoptosis, thus indicating a universal mechanism. P35 has been shown to be a caspase inhibitor with a very wide spectrum of activity both in regard to inhibited caspase types and to species in which the mechanism is conserved.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000169598 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029027 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Liu X, Zou H, Slaughter C, Wang X (April 1997). "DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis". Cell. 89 (2): 175–84. doi: 10.1016/S0092-8674(00)80197-X . PMID   9108473. S2CID   14800864.
  6. ↑ Halenbeck R, MacDonald H, Roulston A, Chen TT, Conroy L, Williams LT (April 1998). "CPAN, a human nuclease regulated by the caspase-sensitive inhibitor DFF45". Current Biology. 8 (9): 537–40. Bibcode:1998CBio....8..537H. doi: 10.1016/S0960-9822(98)79298-X . PMID   9560346. S2CID   9837862.
  7. 1 2 "Entrez Gene: DFFB DNA fragmentation factor, 40kDa, beta polypeptide (caspase-activated DNase)".
  8. 1 2 3 4 Davidson College. "Caspase Activated Deoxyribonuclease (CAD)" . Retrieved 21 Jan 2016.
  9. 1 2 3 4 Yuste VJ, Sánchez-López I, Solé C, Moubarak RS, Bayascas JR, Dolcet X, et al. (October 2005). "The contribution of apoptosis-inducing factor, caspase-activated DNase, and inhibitor of caspase-activated DNase to the nuclear phenotype and DNA degradation during apoptosis". The Journal of Biological Chemistry. 280 (42): 35670–83. doi: 10.1074/jbc.M504015200 . PMID   16049016.
  10. 1 2 3 Sakahira H, Iwamatsu A, Nagata S (March 2000). "Specific chaperone-like activity of inhibitor of caspase-activated DNase for caspase-activated DNase". The Journal of Biological Chemistry. 275 (11): 8091–6. doi: 10.1074/jbc.275.11.8091 . PMID   10713130.
  11. 1 2 3 4 5 Sakahira H, Enari M, Nagata S (May 1999). "Functional differences of two forms of the inhibitor of caspase-activated DNase, ICAD-L, and ICAD-S". The Journal of Biological Chemistry. 274 (22): 15740–4. doi: 10.1074/jbc.274.22.15740 . PMID   10336474.
  12. 1 2 3 Jog NR, Frisoni L, Shi Q, Monestier M, Hernandez S, Craft J, et al. (April 2012). "Caspase-activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens". Arthritis and Rheumatism. 64 (4): 1247–56. doi:10.1002/art.33448. PMC   3292632 . PMID   22127758.
  13. ↑ Widlak P, Lanuszewska J, Cary RB, Garrard WT (July 2003). "Subunit structures and stoichiometries of human DNA fragmentation factor proteins before and after induction of apoptosis". The Journal of Biological Chemistry. 278 (29): 26915–22. doi: 10.1074/jbc.M303807200 . PMID   12748178.
  14. 1 2 3 Reh S, Korn C, Gimadutdinow O, Meiss G (December 2005). "Structural basis for stable DNA complex formation by the caspase-activated DNase". The Journal of Biological Chemistry. 280 (50): 41707–15. doi: 10.1074/jbc.m509133200 . PMID   16236713.
  15. 1 2 Widlak P, Li P, Wang X, Garrard WT (March 2000). "Cleavage preferences of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease) on naked DNA and chromatin substrates". The Journal of Biological Chemistry. 275 (11): 8226–32. doi: 10.1074/jbc.275.11.8226 . PMID   10713148.
  16. 1 2 Sharif-Askari E, Alam A, Rhéaume E, Beresford PJ, Scotto C, Sharma K, et al. (June 2001). "Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation". The EMBO Journal. 20 (12): 3101–13. doi:10.1093/emboj/20.12.3101. PMC   150191 . PMID   11406587.
  17. 1 2 3 Liu X, Zou H, Widlak P, Garrard W, Wang X (May 1999). "Activation of the apoptotic endonuclease DFF40 (caspase-activated DNase or nuclease). Oligomerization and direct interaction with histone H1". The Journal of Biological Chemistry. 274 (20): 13836–40. doi: 10.1074/jbc.274.20.13836 . PMID   10318789.
  18. ↑ Uegaki K, Otomo T, Sakahira H, Shimizu M, Yumoto N, Kyogoku Y, et al. (April 2000). "Structure of the CAD domain of caspase-activated DNase and interaction with the CAD domain of its inhibitor". Journal of Molecular Biology. 297 (5): 1121–8. doi:10.1006/jmbi.2000.3643. PMID   10764577.
  19. ↑ PDB: 1V0D ​; Woo EJ, Kim YG, Kim MS, Han WD, Shin S, Robinson H, et al. (May 2004). "Structural mechanism for inactivation and activation of CAD/DFF40 in the apoptotic pathway". Molecular Cell. 14 (4): 531–9. doi: 10.1016/S1097-2765(04)00258-8 . PMID   15149602.
  20. ↑ "CASP3 caspase 3 [Homo sapiens (human)] - Gene - NCBI".
  21. ↑ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC   1847948 . PMID   17353931.
  22. ↑ McCarty JS, Toh SY, Li P (October 1999). "Study of DFF45 in its role of chaperone and inhibitor: two independent inhibitory domains of DFF40 nuclease activity". Biochemical and Biophysical Research Communications. 264 (1): 176–80. doi:10.1006/bbrc.1999.1497. PMID   10527860.
  23. ↑ Larsen BD, Rampalli S, Burns LE, Brunette S, Dilworth FJ, Megeney LA (March 2010). "Caspase 3/caspase-activated DNase promote cell differentiation by inducing DNA strand breaks". Proceedings of the National Academy of Sciences of the United States of America. 107 (9): 4230–5. Bibcode:2010PNAS..107.4230L. doi: 10.1073/pnas.0913089107 . PMC   2840077 . PMID   20160104.
  24. ↑ Fernando P, Megeney LA (January 2007). "Is caspase-dependent apoptosis only cell differentiation taken to the extreme?". FASEB Journal. 21 (1): 8–17. doi: 10.1096/fj.06-5912hyp . PMID   17093139. S2CID   11933880.
  25. ↑ Fernando P, Kelly JF, Balazsi K, Slack RS, Megeney LA (August 2002). "Caspase 3 activity is required for skeletal muscle differentiation". Proceedings of the National Academy of Sciences of the United States of America. 99 (17): 11025–30. Bibcode:2002PNAS...9911025F. doi: 10.1073/pnas.162172899 . PMC   123204 . PMID   12177420.
  26. ↑ Lai SK, Wong CH, Lee YP, Li HY (June 2011). "Caspase-3-mediated degradation of condensin Cap-H regulates mitotic cell death". Cell Death and Differentiation. 18 (6): 996–1004. doi:10.1038/cdd.2010.165. PMC   3131938 . PMID   21151026.
  27. ↑ Marsden VS, O'Connor L, O'Reilly LA, Silke J, Metcalf D, Ekert PG, et al. (October 2002). "Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome". Nature. 419 (6907): 634–7. Bibcode:2002Natur.419..634M. doi:10.1038/nature01101. PMID   12374983. S2CID   4415828.
  28. 1 2 Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (January 1998). "A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD". Nature. 391 (6662): 43–50. Bibcode:1998Natur.391...43E. doi:10.1038/34112. PMID   9422506. S2CID   4407426.
  29. ↑ McIlroy D, Sakahira H, Talanian RV, Nagata S (August 1999). "Involvement of caspase 3-activated DNase in internucleosomal DNA cleavage induced by diverse apoptotic stimuli". Oncogene. 18 (31): 4401–8. doi: 10.1038/sj.onc.1202868 . PMID   10442630.

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