Chromosome segregation errors: a double-edged sword - TI Pharma

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53BP1 does not depend on gH2AX for its initial recruitment 209 , although its accumulation at DNA
damage foci is affected when the interaction between gH2AX and MDC1 is abrogated in cells 210,212 .
53BP1 and all other repair proteins work together to control genomic stability and loss of any of these
proteins could have disastrous consequences for the damaged cell and, more importantly, for the
whole organism 198 .
3.2 Checkpoint activation
To be able to initiate and complete DSB repair before cells divide, a signaling cascade has evolved that
halts cell cycle progression, called the DNA damage checkpoint. DNA damage checkpoint activation
in G1 ultimately induces the rapid stabilization and accumulation of the tumor suppressor p53.
Although p53 activation is absolutely essential for G1 checkpoint maintenance, additional pathways
exist in S and G2 phase that can delay cell cycle progression 219 involving degradation of cell cycle
regulators such as Cdc25A and Cyclin D1. The main downstream target for transcriptional activation
by p53 is the Cdk inhibitor p21, activation of which results in inhibition of G1 cell cycle progression 220 .
Besides its role in H2AX phosphorylation and recruitment of repair factors, ATM is also essential for
DSB-induced checkpoint activation by phosphorylating several downstream effectors, such as p53,
Chk2 and MDM2. ATM phosphorylates p53 on Serine 15, resulting in stabilization of p53 and enhanced
transactivation of p53 target genes 221-224 . ATM also stabilizes p53 via the activation of its downstream
kinase Chk2. ATM activates Chk2 by phosphorylating it on threonine 68 225,226 and Chk2 on its turn
phosphorylates p53 on serine 20 227-229 . Serine 20 phosphorylation was shown to directly affect the
binding affinity of the E3 ubiquitin ligase MDM2 to p53, therefore resulting in p53 stabilization 227-229 .
Moreover, ATM can also directly phosphorylate and inhibit MDM2 230 . Overall, ATM activation has
been shown to be crucial for G1 checkpoint activation by DSBs and is therefore essential for genomic
stability.
4. Genetic instability
Despite all cell cycle checkpoints that can prevent damaged cells from entering into mitosis or help
to maintain chromosome segregation fidelity, tumor cells typically become genetically unstable, and
continuously undergo changes in their genetic make-up 231 . These changes can range from single base
substitutions to complete chromosome gains or losses.
Figure 5. Typical karyotype of a cancer cell
Karyotype of a human osteosarcoma cell line (U2OS) revealing a variety of numerical and structural chromosomal abnormalities.
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