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Apoptosis and genomic instability

Key Points

  • Genomic instability can be linked to disabled apoptosis, and both phenomena can engage in a positive amplification loop.

  • Genomic instability can disable the apoptotic programme — for example, due to the mutation or deletion of pro-apoptotic genes.

  • The inhibition of apoptosis can favour chromosomal instability (CIN) at several levels. DNA double-strand breaks result in structural CIN when the default pathway that leads to senescence and apoptosis is blocked. Similarly, telomere dysfunction entails rampant structural CIN only when the p53-dependent senescence or apoptosis pathway is disabled.

  • Inactivation of p53 is also permissive for the survival of polyploid cells. Disabling the DNA-structure checkpoint can favour metaphase-associated cell death. Suppression of this 'mitotic catastrophe' by caspase inhibitors or BCL2 overexpression results in asymmetric cell division and aneuploidy. Furthermore, the spindle-assembly checkpoint is functionally linked to apoptosis regulation by BUBR1 (pro-apoptotic) and survivin (anti-apoptotic) proteins.

  • Oncogenic kinases can simultaneously inhibit DNA repair and apoptosis. Moreover, proteins that are involved in DNA repair can participate in the activation of the DNA-damage-induced apoptotic default pathway or, vice versa, apoptosis-regulatory proteins can affect DNA repair.

  • The intricate interplay between apoptosis control and genomic instability is likely to have an important role in oncogenesis. Proteins that determine this interplay include p53, p21 and CHK2, as well as numerous additional effectors that are involved in the DNA-damage and spindle-assembly checkpoints. Such proteins, as well as their immediate afferent and efferent interactors, might constitute therapeutic targets for cancer prevention and treatment.

Abstract

Genomic instability is intrinsically linked to significant alterations in apoptosis control. Chromosomal and microsatellite instability can cause the inactivation of pro-apoptotic pathways. In addition, the inhibition of apoptosis itself can be permissive for the survival and ongoing division of cells that have failed to repair DNA double-strand breaks, experience telomere dysfunction or are in an abnormal polyploid state. Furthermore, DNA-repair proteins can regulate apoptosis. So, genomic instability and apoptosis are intimately linked phenomena, with important implications for the pathophysiology of cancer.

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Figure 1: p53-dependent and p53-independent processes that link double-strand DNA breaks to the apoptotic default pathway.
Figure 2: Telomeric instability.
Figure 3: Relationship between polyploidy and apoptosis.
Figure 4: Mitotic catastrophe as a default pathway to avoid asymmetric division.

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Acknowledgements

The authors' own work is supported by the European Commission.

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DATABASES

Entrez

MSH2

p53

TERC

Swiss-Prot

AIF

ATM

Aurora-A

Aurora-B

BAK

BCL2

BCL-XL

BLM

BRCA1

caspase-2

CD95

CHK1

CHK2

cytochrome c

H2AX

histone H1.2

NUR77

p21

p73

RAD1

survivin

TERT

WRN

Glossary

GENOMIC INSTABILITY

The failure to transmit an accurate copy of the entire genome from one cell to its two daughter cells. Note that this term does not describe a state but, rather, a process.

CENTROSOME

A specialized organelle that duplicates during interphase and that constitutes the centre of the mitotic spindle.

POLYPLOIDY

A situation in which a cell has more than two complete sets of chromosomes in G1 or more than four sets in G2/M: so, triploid cells carry 3N in G1 and tetraploid cells have 4N. Note that polyploidy (not to be confused with hyperploidy, a special case of aneuploidy with too many chromosomes) refers to simple multiples of the normal chromosome number.

CHROMOSOMAL INSTABILITY

(CIN). Genetic changes that are manifested at the level of chromatin maintenance and segregation.

HAPLOINSUFFICIENT

A gene that requires bi-allelic expression. Suppression of one allele would reduce the gene dosage below the critical level.

LINKAGE DISEQUILIBRIUM

Non-independent assortment of genes during cell division; for example, because they are situated on the same chromosome.

MICROSATELLITE INSTABILITY

(MSI). Alterations in the length of short repetitive sequences (microsatellites), which can be detected by the PCR amplification of tumour DNA. After PCR, new bands that were not present in PCR products of the corresponding normal DNA will appear if MSI has occurred.

BCL2 FAMILY

A family of proteins that all contain at least one BCL2 homology (BH) region. The family is divided into anti-apoptotic multidomain proteins (such as BCL2 and BCL-XL), which contain four BH domains (BH1, BH2, BH3, BH4), pro-apoptotic multidomain proteins (for example, BAX and BAK), which contain BH1, BH2 and BH3, and the pro-apoptotic BH3-only protein family (for example, BID, BIM and PUMA).

ANEUPLOIDY

The ploidy of a cell refers to the number of chromosome sets that it contains. Aneuploid karyotypes are chromosome complements that are not a simple multiple of the haploid set.

NON-HOMOLOGOUS END JOINING

(NHEJ). The main pathway that is used throughout the cell cycle to repair chromosomal double-strand DNA breaks in somatic cells. In contrast to homologous-recombination repair, NHEJ is error-prone because it leads to the joining of heterologous ends.

DICENTRIC CHROMOSOME

A chromosome that carries two centromeres, which arise from the aberrant fusion of 'naked' telomeres or interstitial double-strand breaks.

BREAKAGE-FUSION-BRIDGE (BFB) CYCLE

Dicentric chromosomes — which are generated by the fusion of two centrosome-containing chromosome fragments or two 'naked' telomeres — break apart in mitosis, after which they fuse again, forming a mutated dicentric chromosome.

APOPTOSOME

A complex that forms when cytochrome c is released from mitochondria and interacts with the cytosolic protein APAF1, which, in turn, recruits pro-caspase-9. In the presence of dATP, this interaction results in the allosteric activation of caspase-9 and in the formation of a caspase-3 activation complex.

MITOCHONDRIAL-MEMBRANE PERMEABILIZATION

(MMP). A pro-apoptotic process whereby mitochondrial membranes undergo transient and stable permeabilization and become structurally reorganized. As a result, proteins that are normally retained in the intermembrane space are released through the outer membrane and the bioenergetic function of mitochondria is compromised.

CASPASE

A family of cysteine proteases that cleave after asparagine residues. Initiator caspases are typically activated in response to particular stimuli (for example, caspase-8 after death-receptor ligation, caspase-9 after apoptosome activation, caspase-2 after DNA damage and PIDD activation), whereas effector caspases (mainly caspase-3, -6 and -7) are particularly important for the ordered dismantling of vital cellular structures.

SENESCENCE

A nearly irreversible stage of permanent G1 cell-cycle arrest, which is linked to morphological changes (flattening of the cells), metabolic changes and changes in gene expression (for example, β-galactosidase). The induction of senescence depends on p53 and cell-cycle inhibitors such as p21 and p16.

ENDOREPLICATION

The replication of DNA during S phase of the cell cycle without the subsequent completion of mitosis.

PASSENGER PROTEIN

A protein that shares a characteristic pattern of association with chromatin in prophase, centromeres in metaphase and early anaphase, and then the midzone and midbody in late anaphase and telophase, respectively.

ANISOCYTOSIS

Abnormal heterogeneity in cell size.

ANISOKARYOSIS

Abnormal heterogeneity in nuclear size and/or in the cytoplasm:nucleus ratio.

DNA-STRUCTURE CHECKPOINT

A checkpoint that arrests cell-cycle advancement until DNA mutations such as double-strand breaks are repaired, or until the replication of complementary strands has been completed.

CYTOCHROME C

A haem protein that is normally confined to the mitochondrial intermembrane space. Following induction of apoptosis, cytochrome c is released from mitochondria and triggers the formation of the apoptosome, a caspase-activation complex.

APOPTOSIS-INDUCING FACTOR

(AIF). A flavoprotein that is normally present in the mitochondrial intermembrane space. Following the induction of apoptosis, AIF translocates to the nucleus where it activates a molecular complex that causes large-scale DNA fragmentation, presumably in a caspase-independent fashion.

SYNCYTIUM

A cytoplasm that contains several nuclei within the same plasma membrane and without internal cell boundaries. Syncytia are mostly generated by cell fusion.

KARYOKINESIS

The physical separation of the daughter nuclei at the end of mitosis.

SPINDLE-ASSEMBLY CHECKPOINT

A checkpoint that monitors the correct attachment of chromosomes to spindles in the metaphase–anaphase transition. Activation of this checkpoint causes cell-cycle arrest as a result of the inhibition of anaphase-promoting complex/cyclosome (APC/C) and is mediated by a cytoplasmic activity known as cytostatic factor (CSF).

KINETOCHORE

A specialized condensed chromosomal region in which the chromatids are held together to form an X shape.

SMAC/DIABLO

A mitochondrial intermembrane protein that, on apoptotic release, can interact with inhibitor of apoptosis (IAP) proteins such as XIAP, thereby inhibiting their function and facilitating caspase activation.

BASE-EXCISION REPAIR

(BER). The main pathway that is responsible for the repair of apurinic and apyrimidinic (AP) sites in DNA. BER is catalyzed in four consecutive steps by a DNA glycosylase, which removes the damaged base; an AP endonuclease, which processes the abasic site; a DNA polymerase, which inserts the new nucleotide(s); and DNA ligase, which rejoins the DNA strand.

NUCLEOTIDE-EXCISION REPAIR

(NER). A process in which a small region of the DNA strand that surrounds DNA damage is removed from the DNA helix as an oligonucleotide.

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Zhivotovsky, B., Kroemer, G. Apoptosis and genomic instability. Nat Rev Mol Cell Biol 5, 752–762 (2004). https://doi.org/10.1038/nrm1443

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