48
Pérez- Plasencia 2017). DSBs are not caused directly by UV rays (Yajima et al.
2009), but they have been reported, even after low doses of radiation (Federico et al.
2016). Studies on human cell cultures showed that DSBs after UV radiation are created when the machinery responsible for the DNA replication abuts a photoproduct
(Federico et al. 2016). Supporting the appearance of DSBs, the levels of a protein
that are activated when DSBs are formed (the histone variant H2AX) increased in a
manner dependent on UV dose. H2AX plays an essential role in the recruitment and
accumulation of DNA repair proteins to sites of DSB damage (Fernandez-Capetillo
et al. 2003). Moreover, another marker of DSBs as the phosphorylation of ATM
kinase (pATM) showed a similar pattern. During DNA synthesis, DSBs are resolved
by an error-free mechanism (i.e., a mechanism that does not alter DNA sequence)
called homologous recombination repair (HRR). The protein FANCD2, member of
a DNA repair mechanism called Fanconi pathway, promotes HRR of UV-triggered
DSBs by recruiting Rad51 into the damaged site. When FANCD2 or Rad51 are
absent, HRR is not available, and an alternative and very mutagenic pathway takes
charge of DSBs resolution (Federico et al. 2016). This alternative pathway, called
non-homologous end joining, induces genomic instability by the elimination of
some DNA fragments, the addition of extra nucleotides to the sequence, and/or the
fusion of one DNA molecule with a second one.
Fanconi anemia patients (which have failure on the Fanconi pathway) present
several skin-associated defects including hypo-/hyperpigmentation and café au lait
spots (Federico et al. 2016). These characteristics evince a central role of the Fanconi
pathway on the DDR after UV radiation.
The DNA molecule can be degraded after prolonged DNA duplication stalling,
i.e., the nucleotides of the DNA sequence are separated from each other, and the
DNA molecule is shortened (Schlacher et al. 2011). This event has also been
described after UV radiation, and Rad51 has a central role in this process. Rad51
protects DNA from degradation and avoids excessive elongation of nascent DNA
after UV rays (Vallerga et al. 2015). This mechanism is an example of the complexity of DNA synthesis regulation across UV damage. Thus, more research is required
to elucidate the complex network activated when DNA is damaged by UV rays.
4.2.2.2.3 DNA Damage Checkpoint
The cell cycle is the event through which a cell duplicates its genetic material and
all its components and divides into two identical daughter cells. In order to allow a
proper cell cycle progression, cells have developed “checkpoints.” In response to
DNA damage, the cells stop cycling by activating checkpoint machinery, thus allowing DNA repair systems to correct replication errors. If the DNA errors are repaired,
checkpoint signals will disappear, and the cell cycle will be restarted. If the DNA
damage cannot be properly repaired, cell fate includes cell death or replication of
aberrant DNA into subsequent cell progeny (Wang et al. 2015). Therefore, the
checkpoint system is an essential cellular component guarding the integrity of
essential genetic information. The DNA damage checkpoint network contains
M. B. Federico
Pérez- Plasencia 2017). DSBs are not caused directly by UV rays (Yajima et al.
2009), but they have been reported, even after low doses of radiation (Federico et al.
2016). Studies on human cell cultures showed that DSBs after UV radiation are created when the machinery responsible for the DNA replication abuts a photoproduct
(Federico et al. 2016). Supporting the appearance of DSBs, the levels of a protein
that are activated when DSBs are formed (the histone variant H2AX) increased in a
manner dependent on UV dose. H2AX plays an essential role in the recruitment and
accumulation of DNA repair proteins to sites of DSB damage (Fernandez-Capetillo
et al. 2003). Moreover, another marker of DSBs as the phosphorylation of ATM
kinase (pATM) showed a similar pattern. During DNA synthesis, DSBs are resolved
by an error-free mechanism (i.e., a mechanism that does not alter DNA sequence)
called homologous recombination repair (HRR). The protein FANCD2, member of
a DNA repair mechanism called Fanconi pathway, promotes HRR of UV-triggered
DSBs by recruiting Rad51 into the damaged site. When FANCD2 or Rad51 are
absent, HRR is not available, and an alternative and very mutagenic pathway takes
charge of DSBs resolution (Federico et al. 2016). This alternative pathway, called
non-homologous end joining, induces genomic instability by the elimination of
some DNA fragments, the addition of extra nucleotides to the sequence, and/or the
fusion of one DNA molecule with a second one.
Fanconi anemia patients (which have failure on the Fanconi pathway) present
several skin-associated defects including hypo-/hyperpigmentation and café au lait
spots (Federico et al. 2016). These characteristics evince a central role of the Fanconi
pathway on the DDR after UV radiation.
The DNA molecule can be degraded after prolonged DNA duplication stalling,
i.e., the nucleotides of the DNA sequence are separated from each other, and the
DNA molecule is shortened (Schlacher et al. 2011). This event has also been
described after UV radiation, and Rad51 has a central role in this process. Rad51
protects DNA from degradation and avoids excessive elongation of nascent DNA
after UV rays (Vallerga et al. 2015). This mechanism is an example of the complexity of DNA synthesis regulation across UV damage. Thus, more research is required
to elucidate the complex network activated when DNA is damaged by UV rays.
4.2.2.2.3 DNA Damage Checkpoint
The cell cycle is the event through which a cell duplicates its genetic material and
all its components and divides into two identical daughter cells. In order to allow a
proper cell cycle progression, cells have developed “checkpoints.” In response to
DNA damage, the cells stop cycling by activating checkpoint machinery, thus allowing DNA repair systems to correct replication errors. If the DNA errors are repaired,
checkpoint signals will disappear, and the cell cycle will be restarted. If the DNA
damage cannot be properly repaired, cell fate includes cell death or replication of
aberrant DNA into subsequent cell progeny (Wang et al. 2015). Therefore, the
checkpoint system is an essential cellular component guarding the integrity of
essential genetic information. The DNA damage checkpoint network contains
M. B. Federico