NHEJ CtlP to facilitate MH searches (77-79). The

NHEJ is a major
mechanism of DSBR (68). The Ku complex, a heterodimer of two
protein subunits Ku70 and Ku80, acts as a sensor for DSBs. The presence of Ku
complex at the DNA ends of DSB is essential for subsequent DNA end processing
and ligation (69, 70). DNA-dependent protein kinase catalytic
subunit (DNA-PKcs) is recruited to Ku at DNA ends of DSB, becomes activated and
catalyzes synapsis of the DNA ends by dimerization (69, 70). 
Another core complex, XRCC4-lig4-XRCC4 like factor (XLF), is recruited
to sites of damage. XRCC4-lig4-XLF induces DNA-PKcs autophosphorylation,
dissociation, translocation of the Ku heterodimer along the DNA away from the
ends, and recruitment of end processing factors (70). A number of end processing enzymes and
polymerases are recruited to the site of damage by interacting with the core
complex (62,
70, 71). PNKP is one of the key enzymes required for the processing of
DSBs.  PNKP is recruited to the site of
damage by interacting with phosphorylated XRCC4 via the PNKP FHA domain (72). 
Ligation of DNA ends is catalyzed by lig4. Finally, the Ku complex is
removed from DNA ends by proteasomal degradation mediated by ubiquitination by
Cullin and RNF8 (70). Figure 1.3 shows a model depicting the
steps involved in the conventional NHEJ pathway.

A substitute
of classical NHEJ, alt-NHEJ, is available when the cell is deficient in NHEJ
components and relies on microhomology (MH), the tendency of the two DNA ends
to align themselves at short regions of homology within the two ends (73-75). The main attributes of alt-NHEJ are large
deletions, insertions and a high frequency of chromosomal translocations (76). The damage is detected in this situation by
PARP-1, which facilitates the recruitment of the MRN complex to bridge the DNA ends,
following the loading of CtlP to facilitate MH searches (77-79). The ligation process is mainly driven by
the activity of the XRCC1/lig3 complex and on some occasions lig1, where MH is
not required (80). In recent studies, it was shown that
polymerase ? (Pol ?) performs terminal transferase activity at the 3?-termini of resected DSBs to mediate MH (81,
82). PNKP is also involved in this process and is likely partially
regulated by IR-induced phosphorylation of PNKP
by Ataxia telangiectasia mutated (ATM) and DNA-PKcs (83,
84). An in vivo study showed
that the inactivation of DNA-PKcs and/or ATM led to reduced PNKP levels at DNA
damage sites (84). Based on the observation that depletion of
PNKP does not alter the level of sister chromatid exchanges, it was surmised
that PNKP does not participate in HR, the other major DSB repair pathway (85).

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