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DNA ligase III and DNA ligase IV carry out genetically distinct forms of end
joining in human somatic cells
#MMPMID24837021
Oh S
; Harvey A
; Zimbric J
; Wang Y
; Nguyen T
; Jackson PJ
; Hendrickson EA
DNA Repair (Amst)
2014[Sep]; 21
(?): 97-110
PMID24837021
show ga
Ku-dependent C-NHEJ (classic non-homologous end joining) is the primary DNA EJing
(end joining) repair pathway in mammals. Recently, an additional EJing repair
pathway (A-NHEJ; alternative-NHEJ) has been described. Currently, the mechanism
of A-NHEJ is obscure although a dependency on LIGIII (DNA ligase III) is often
implicated. To test the requirement for LIGIII in A-NHEJ we constructed a LIGIII
conditionally-null human cell line using gene targeting. Nuclear EJing activity
appeared unaffected by a deficiency in LIGIII as, surprisingly, so were random
gene targeting integration events. In contrast, LIGIII was required for
mitochondrial function and this defined the gene's essential activity. Human
Ku:LIGIII and Ku:LIGIV (DNA ligase IV) double knockout cell lines, however,
demonstrated that LIGIII is required for the enhanced A-NHEJ activity that is
observed in Ku-deficient cells. Most unexpectedly, however, the majority of EJing
events remained LIGIV-dependent. In conclusion, although human LIGIII has an
essential function in mitochondrial maintenance, it is dispensable for most types
of nuclear DSB repair, except for the A-NHEJ events that are normally suppressed
by Ku. Moreover, we describe that a robust Ku-independent, LIGIV-dependent repair
pathway exists in human somatic cells.
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